The Metastatic Breast Cancer Project: Leveraging Patient-Partnered Research to Expand the Clinical and Genomic Landscape of Metastatic Breast Cancer and Accelerate Discoveries

Capturing the full complexity of the clinical experiences of metastatic breast cancer (MBC) patients treated in a variety of settings is needed to better understand this disease and develop new treatment modalities. Yet, challenges exist to establish and share a large MBC dataset that integrates genomic, clinical, and patient-reported data as it requires collecting information and samples from many geographically dispersed patients and institutions. We explored whether a patient-partnered research approach that uses online engagement could enable patients living across the United States and Canada to accelerate cancer research by sharing their samples, clinical information, and experiences. In collaboration with patients and patient advocates, the Metastatic Breast Cancer Project (MBCproject; [www.mbcproject.org][1]) was developed and launched in October 2015. As of March 2020, 3,246 MBC patients who received treatment at ∼1,700 institutions had consented for the MBCproject, providing patient-reported information via surveys, as well as access to medical records and biological samples. Through the collection and analysis of tumor and germline samples, medical records, and patient-reported data, the MBCproject generates and publicly releases clinically-annotated genomic data on primary and metastatic tumor specimens on a recurring basis. Herein we describe the MBCproject cohort in detail and describe the clinico-genomic landscape of the MBCproject dataset. The complete dataset consists of whole exome sequencing (WES) for 379 tumors with matching germline from 301 patients, WES on germline samples from 377 patients, and transcriptome sequencing (RNA-seq) for 200 tumors from 141 patients, with clinical data from medical records and patient-reported information. A comparison of various clinical fields (diagnostic dates, tumor histology, tumor sites, treatments received) obtained from patient-reported data and the abstracted from medical records found a high degree of concordance, with multiple fields having over 90% concordance. Analysis of the somatic alterations in the 249 tumors taken after metastatic diagnosis found a significant enrichment of mutations in the cancer genes TP53 , PIK3CA , CDH1 , PTEN, AKT1, NF1 , and ESR1 , among others. Tumor evolutionary analysis of 14 patients with 3 or more samples identified oncogenic mutations in ESR1 , NF1 , and TP53 , genes associated with MBC and/or resistance to endocrine therapy. Analysis of germline samples identified pathogenic variants in the cancer-associated genes BRCA1, BRCA2 , ATM, and PALB2 . Comparing the frequency of pathogenic variants in patients diagnosed before/at or after the age of 40 years old, we found that the presence of these variants in BRCA1 or BRCA2 was enriched in the younger group compared to the older group (9.2% vs 2.5%, p=0.0089; two-sided Fisher exact test). Transcriptome sequencing identified putatively oncogenic in-frame fusions in cancer genes such as FANCD2 , FGFR3 , ESR1 , BRAF and NCOR1 . Analysis of tumor’s intrinsic molecular subtype (research-based PAM50) found a depletion of the Luminal A subtype in MBCproject compared to The Cancer Genome Atlas, and a switch in molecular subtype in 15 out of 35 patients with 2 or more samples. A case study of a patient with sequencing data from 4 tumor biopsies obtained during the course of their metastatic disease is presented. An integrated analysis of the clinical and multi-omic data from this patient identified distinct drivers of resistance to endocrine therapy in each of these tumors. The MBCproject clinico-genomic dataset is one of the largest available MBC patient cohorts This integrated dataset is poised for studying several understudied clinical cohorts (young women with breast cancer, de novo MBC), rare disease subtypes (e.g. lobular, metaplastic, extraordinary responders), biomarkers of response/resistance (e.g. CDK4/6 inhibitors), and real world patterns, among others, and will serve as an invaluable resource to accelerate discoveries. ### Competing Interest Statement JG owns stocks in the biotechnology exchange-traded funds CNCR, IDNA, IBB, and XBI, and owned stocks in Adaptive Biotechnologies, 2seventy bio, and bluebird bio. EJ is a current employee of Repare Therapeutics. SB is a current employee of GRAIL Inc.. JEB-B is a current employee of Cellarity. EMV reports advisory/consulting from Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics, and Serinus Bio; research support from Novartis, BMS, and Sanof; equity from Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics, and Serinus Bio; institutional patents on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag; being on the Editorial Board of JCO Precision Oncology and Science Advances. TRG is a co-founder, holds equity, and was previously a scientific advisor in Sherlock Biosciences, Inc.; receives compensation from Anji Oncology (cash and equity), Braidwell (cash), Dewpoint Therapeutics (cash and equity); received compensation from GlaxoSmithCline (unpaid as of January 2021). CAP is a current employee at Precede Biosciences. NW is an employee of Genentech as of Feb 13, 2023 and has equity in Roche; holds equity in Relay Therapeutics and Flare Therapeutics; is a consultant for Flare Therapeutics; prior to Jan 31 2023 was a scientific advisory board member of Relay Therapeutics, an advisory board member for Eli Lilly, and received research support from Astra-Zeneca and Puma Biotechnologies. The remaining authors declare no conflicts of interest. ### Funding Statement This research was supported by the non-profit organization Count Me In (joincountmein.org) and by anonymous philanthropic support to the Broad Institute. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional review board (IRB) of Dana-Farber/Harvard Cancer Center (DF/HCC) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The clinically annotated genomic dataset of the MBCproject is shared publicly in order for all researchers to be able to utilize this data to better understand metastatic breast cancer. De-identified data has been shared on a recurring basis as the data is generated. Data from The Metastatic Breast Cancer Project is available at cBioPortal (https://www.cbioportal.org/study/summary?id=brca\_mbcproject\_2022), National Cancer Institute's Genomic Data Commons (https://portal.gdc.cancer.gov/projects/CMI-MBC) and dbGaP (Study Accession phs001709). cBioPortal has the clinical and genomic data for the MBCproject clinico-genomic dataset (N=379 tumor, 301 patients). As of May 1st 2023, updating the Genomic Data Commons and dbGaP data repositories with the genomic data for all the tumor samples used in this study is in progress. The clinically annotated genomic dataset of the MBCproject is shared publicly in order for all researchers to be able to utilize this data to better understand metastatic breast cancer. De-identified data has been shared on a recurring basis as the data is generated. Data from The Metastatic Breast Cancer Project is available at cBioPortal ([https://www.cbioportal.org/study/summary?id=brca\_mbcproject\_2022][2]), National Cancer Institute's Genomic Data Commons () and dbGaP (Study Accession phs001709). cBioPortal has the clinical and genomic data for the MBCproject clinico-genomic dataset (N=379 tumor, 301 patients). As of May 1st 2023, updating the Genomic Data Commons and dbGaP data repositories with the genomic data for all the tumor samples used in this study is in progress. [1]: http://www.mbcproject.org [2]: https://www.cbioportal.org/study/summary?id=brca_mbcproject_2022