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) 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 genesTP53,PIK3CA,CDH1,PTEN,AKT1,NF1, andESR1, among others. Tumor evolutionary analysis of 14 patients with 3 or more samples identified oncogenic mutations inESR1,NF1, andTP53, genes associated with MBC and/or resistance to endocrine therapy. Analysis of germline samples identified pathogenic variants in the cancer-associated genesBRCA1,BRCA2,ATM, andPALB2. 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 inBRCA1orBRCA2was 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 asFANCD2,FGFR3,ESR1,BRAFandNCOR1. 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 novoMBC), 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.
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. Note: To assist our patient-partners and the wider MPC community interpret the results of this study, we have attached a supplemental glossary of terms.
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 <40 yrs of age (1108 pts enrolled; 120 with tumor WES) - de novo MBC (1122 pts enrolled; 121 with tumor WES) - Late recurrence, >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.
The Metastatic Breast Cancer Project (MBCproject) is an ongoing 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. 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 US or Canada to register. From 10/20/15-3/31/20, 5708 women and men with MBC registered for the MBCproject. Registered pts are sent an online consent form that asks for permission to obtain and analyze their medical records and samples. Consented pts are sent a saliva and/or 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 to obtain medical records and a portion of their stored tumor biopsies. 3245 pts receiving care at over 1700 different institutions have consented to share medical records and tumor/saliva/blood samples and to have genomic analysis performed. 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. Table 1 highlights clinical data collection, biospecimen acquisition, and genomic data generation to date. Examples of clinicogenomic analyses are shown in Table 2. De-identified linked genomic, clinical, and pt-reported data is shared regularly via public and semi-public databases (mbcproject.org, cBioPortal, dbGaP, NCI Genomic Data Commons). To date, this data has been cited in over 20 published journal articles. Study updates are shared with participants regularly. The MBCproject continues to enroll new patients, generate additional data, and perform integrated clinical and genomic analyses with the goal of building a dataset that is representative of patients with MBC. We have partnered with over 30 non-profit breast cancer advocacy groups. We also have several community engagement efforts underway to more directly reach patients in underrepresented communities, including partnerships with faith-based organizations and colleges/universities, as well as targeted engagement with the African American community. In addition, in partnership with Latinx patients, advocates, and researchers, the project has been translated into Spanish and is expected to launch in late 2020. Partnering directly with pts rapidly enables thousands of pts to remotely share tumors, blood, saliva, and medical records to accelerate research. The resulting publicly shared clinically annotated database is a resource that allows researchers to identify patients with specific phenotypes, who have often been challenging to identify with traditional approaches. Clinical data collection, biospecimen acquisition, and genomic data generation:NumberConsent signed (US & CA)3245 ptsSurvey #1 submitted(demographics, diagnosis details, receptor status, clinical experiences)3245 ptsSurvey #2 submitted(pathology details, sites of metastasis, treatments with start and stop dates)1638 ptsMedical record received1352 ptsSaliva sample received2004 ptsBlood sample received1121 ptsTumor samples received585 tumor samples from 424 ptsDigital image of tumor slide H&E generated585 tumor samplesWES from germline complete458 germline samplesWES from tumor (primary and metastatic) samples complete343 tumor samplesRNA-seq from tumor (primary and metastatic) samples complete228 tumor samplesULP-WGS from cfDNA (taken in metastatic setting) complete993 blood samplesWES from circulating tumor DNA (taken in metastatic setting) complete143 blood samples CohortConsented (US & CA)Tumor WES completeTumor RNA-seq completePts diagnosed < 40 yrs of age107312071De novo MBC112712183Late recurrence (>5 years after dx)8307752Long term survivors (MBC > 10yrs)158115Resistance to CDK4/6 inhibitors70914839NED at time of f/u survey4238939Triple Negative Breast Cancer3107531Patients with 2 or more tumor biopsies / cfDNA samples collected by the MBCproject2876138 Citation Format: Nikhil Wagle, Corrie Painter, Elana Anastasio, Michael Dunphy, Mary McGillicuddy, Esha Jain, Brett Tomson, Tania G. Hernandez, Beena Thomas, Dewey Kim, Alyssa L. Damon, Shahrayz Shah, Rafael Ramos, Colleen Nguyen, Lee O'Neil, Sarah Winnicki, Sara Balch, Rachel Stoddard, Taylor Cusher, Parker Chastain, Jorge Gomez Tejeda Zanudo, Jorge Buendia-Buendia, Ofir Cohen, Netsanet Tsegai, Lauren Sterlin, Ulcha F. Ulysse, Imani Boykin, Kate 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 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-18-01.
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