The Prostate Cancer Project (PC Project): Translational genomics through direct patient engagement.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 199-199
Author(s):  
Stephanie Anne Mullane ◽  
Corrie Painter ◽  
Michael Dunphy ◽  
Elana Anastasio ◽  
Tania Simoncelli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Success Rate ◽  
Medical Records ◽  
Tumor Tissue ◽  
Metastatic Breast ◽  
Community Setting ◽  
Circulating Tumor Dna ◽  
Blood Draw ◽  
Study Results ◽  
Cancer Project

199 Background: While there has been substantial advancement in the genomic understanding of prostate cancer (PCa), there is still much to be discovered. Additional progress is dependent upon obtaining a large amount of clinically annotated genomic data. As PCa is often treated in a community setting, where research samples are not collected, we are starting a direct-to-patient nationwide research initiative where patients can donate their medical records and biospecimens to accelerate research. Previously, we launched the metastatic breast cancer project (MBCproject; mbcproject.org) that leverages social media to engage the MBC community. Based on the initial success with this approach, we now aim to build out the PCproject. Methods: In collaboration with patients, we are developing a website to enable participation in the PCproject. Enrolled patients will be sent a saliva kit, used for germline DNA. We will also obtain medical records. Metastatic patients will also be sent a blood draw kit for circulating tumor DNA (ctDNA). Whole exome sequencing of the ctDNA will be performed. We will use the recruitment infrastructure, clinical record abstraction, and biospecimen processing developed for the MBC project. The data will be shared widely with the research community. Aggregate study results will be reported to patients. Results: In the first year of the MBCproject, 2912 MBC patients from all 50 states enrolled. 2766 (95.0%) completed the 16-question survey about their cancer, treatments, and demographic information. 1716 (58.9%) completed the online consent form permitting acquisition and analysis of medical records, tumor tissue, and saliva samples. 936 (68.8% success rate) saliva samples have been received. To date, we have obtained medical records from 155 patients (72.1% success rate) and tumor samples from 60 patients (72.3% success rate). Based on initial recruitment and surveys among PCa patients, we estimate that 500 patients will enroll in 2017. Conclusions: Based on experience from the MBC project, we will partner directly with patients to recruit and drive the PCproject forward. Remote acquisition of medical records, saliva samples, and tumor tissue for patients located throughout the US is feasible.

Performance of a high-intensity 508-gene circulating-tumor DNA (ctDNA) assay in patients with metastatic breast, lung, and prostate cancer.

2017 ◽  
Vol 35 (18_suppl) ◽  
pp. LBA11516-LBA11516 ◽  
Author(s):  
Pedram Razavi ◽  
Bob T. Li ◽  
Wassim Abida ◽  
Alex Aravanis ◽  
Byoungsok Jung ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Detection ◽  
High Intensity ◽  
Tumor Tissue ◽  
De Novo ◽  
Early Cancer ◽  
Metastatic Breast ◽  
Early Cancer Detection ◽  
Driver Mutations ◽  
Castration Resistant Prostate Cancer

LBA11516 Background: ctDNA assays can noninvasively assess tumor burden and biology by identifying tumor-derived somatic alterations. For broad applicability, including early cancer detection, an unprecedented high-intensity approach (ultra-deep sequencing of plasma cell-free DNA (cfDNA) with broad genomic coverage) is needed to address intra-patient and population-level heterogeneity. We present initial results with this approach in patients (pts) with metastatic breast (BC), non-small cell lung (NSCLC), and castration-resistant prostate cancer (CRPC). Methods: Blood and tissue were prospectively collected w/in 6 wks with no intervening therapy change from pts with de novo or progressive cancer. cfDNA and white blood cell (WBC) genomic DNA from each pt were sequenced with a 508-gene panel (2 Mb; >60,000X raw depth). cfDNA variant calling used molecular barcoding for error correction and filtering for WBC variants. Tissue was sequenced using the MSK-IMPACT assay (410 genes, 1.4 Mb, >500X depth) blinded to plasma/WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in BC and NSCLC. Results: Of 161 eligible pts, 124 (39 BC, 41 NSCLC, and 44 CRPC) were evaluable for concordance. In tissue, 864 variants were detected across the 3 tumor types, with 627 (73%) also detected in plasma: single nucleotide variants/indels - 75%, fusions - 67%, and copy number alterations - 58%. In 90% of pts, at least 1 of the variants detected in tumor tissue was also detected in plasma: BC - 97%, NSCLC - 85%, CRPC - 84%. Most actionable mutations detected in tissue were also detected in plasma (54/71, 76%; SNVs only: 28/31, 90%). A subset of driver mutations (eg. in ESR1, PIK3CA, ERBB2, EGFR) were observed in plasma but not tissue. Clonal variants in tissue were more likely to be detected in plasma than subclonal variants (p<.001). Conclusions: This novel, high-intensity ctDNA assay enabled broad detection of genomic variants in plasma at high rates of concordance with corresponding tumor tissue, providing strong evidence for tumor-derivation of these signals. This study will inform development of a high-intensity sequencing approach for early cancer detection.

scholarly journals ESR1 Gene Mutation in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer Patients: Concordance Between Tumor Tissue and Circulating Tumor DNA Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Loredana Urso ◽  
Grazia Vernaci ◽  
Jessica Carlet ◽  
Marcello Lo Mele ◽  
Matteo Fassan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Hormone Receptor ◽  
Liquid Biopsy ◽  
Tumor Tissue ◽  
Metastatic Breast ◽  
Metastatic Tumor ◽  
Circulating Tumor Dna ◽  
Hormone Receptor Positive ◽  
Tumor Dna

Endocrine therapy represents the cornerstone of treatment in hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (mBC). The natural course of this disease is marked by endocrine resistance, mainly due to Estrogen Receptor 1 (ESR1) acquired mutations. The aim of this study is to evaluate the concordance between ESR1 status in metastatic tumor specimens and matched circulating tumor DNA (ctDNA). Forty-three patients with HR+, HER2-negative mBC underwent both a metastatic tumor biopsy and a liquid biopsy at the time of disease progression. DNA extracted from formalin fixed paraffin embedded (FFPE) tumor specimens and ctDNA from matched plasma were analyzed by droplet digital (dd)PCR for the main ESR1 mutations (Y537S, Y537C, Y537N, D538G, E380Q). We observed a total mutation rate of 21%. We found six mutations on tissue biopsy: Y537S (1), D538G (2), Y537N (1), E380Q (2). Three patients with no mutations in tumor tissue had mutations detected in ctDNA. The total concordance rate between ESR1 status on tumor tissue and plasma was 91%. Our results confirm the potential role of liquid biopsy as a non-invasive alternative to tissue biopsy for ESR1 mutation assessment in mBC patients.

Performance of a high-intensity 508-gene circulating-tumor DNA (ctDNA) assay in patients with metastatic breast, lung, and prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. LBA11516-LBA11516 ◽  
Author(s):  
Pedram Razavi ◽  
Bob T. Li ◽  
Wassim Abida ◽  
Alex Aravanis ◽  
Byoungsok Jung ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Annual Meeting ◽  
Clinical Oncology ◽  
High Intensity ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Daily News ◽  
Online Supplement ◽  
Tumor Dna ◽  
Final Text

LBA11516 The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Saturday, June 3, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.

The Metastatic Prostate Cancer project (MPCproject): Translational genomics through direct patient engagement.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 279-279 ◽  
Author(s):  
Stephanie Anne Mullane ◽  
Corrie Painter ◽  
Michael Dunphy ◽  
Elana Anastasio ◽  
Tania Simoncelli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Informed Consent ◽  
Medical Records ◽  
Metastatic Prostate Cancer ◽  
De Novo ◽  
Secondary Malignancy ◽  
Blood Samples ◽  
Study Results ◽  
Patient Reported ◽  
Reported Data

279 Background: While there has been substantial advancement in the genomic understanding of metastatic prostate cancer (MPC), there is still much to be discovered. Additional progress is dependent upon obtaining a large amount of clinically-annotated genomic data. Therefore, we piloted a direct-to-patient nationwide research initiative where patients can contribute their medical records and biospecimens to accelerate research ( mpcproject.org ). Methods: In collaboration with patients and advocacy groups, we have developed a website ( mpcproject.org ). Participants are asked to complete a 17-question survey about their experiences with prostate cancer and an electronic informed consent. All participants receive a saliva kit for germline DNA and blood kit for circulating tumor DNA (ctDNA). Additionally, medical records are collected and archived tissue samples are requested if available. Ultra low pass whole genome sequencing (ULP-WGS) and whole exome sequencing (WES) are performed on the whole blood samples. WES is performed on saliva samples. Genomic, clinical, and patient-reported data will be shared widely with the research community. Aggregate study results will be reported to patients. Results: As of October 2017, 12 pilot patients aged 47-74 from 7 states, provided informed consent. 7 saliva kits, 4 blood kits, and 2 medical records were received. 4 patients were diagnosed with de novo metastatic disease, 8 reported a family history of breast and/or prostate cancer, 6 reported a secondary malignancy. All blood kits were submitted for ULP-WGS and WES. Updated genomic, clinical, and patient-reported data will be presented. Conclusions: We have provided preliminary evidence that partnering directly with MPC patients enabled the remote collection of saliva and blood samples, medical records, and patient-reported data. At the conclusion of the pilot phase, the MPC Project will open enrollment for all men with metastatic and advanced prostate cancer in the US and Canada.

The Metastatic Breast Cancer Project: A national direct-to-patient initiative to accelerate genomics research.

2016 ◽  
Vol 34 (18_suppl) ◽  
pp. LBA1519-LBA1519 ◽  
Author(s):  
Nikhil Wagle ◽  
Corrie Painter ◽  
Max Krevalin ◽  
Coyin Oh ◽  
Kristin Anderka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Median Time ◽  
Medical Records ◽  
De Novo ◽  
Saliva Sample ◽  
Metastatic Breast ◽  
Genomic Analysis ◽  
Tumor Biopsy ◽  
Cancer Project

LBA1519 Background: The challenge in studying tumors from patients (pts) with metastatic breast cancer (MBC) has been that most tumors are not available for research, largely because most pts are cared for in community settings where genomics studies are not conducted. To address this, we launched a nationwide study, The Metastatic Breast Cancer Project, which seeks to empower patients to accelerate research by sharing their samples and clinical information. Methods: In collaboration with pts and advocacy groups, we developed a website to allow MBC pts to participate across the U.S. 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 part of their tumor biopsy. Whole exome and transcriptome sequencing is performed on tumor and germline. Clinically annotated genomic data are used to identify mechanisms of response and resistance to therapies. The database is shared widely with researchers. Study updates and discoveries are shared with participants regularly. Results: In the first 3 months, 1227 MBC pts enrolled. 1178 (96%) completed the 16-question survey about their cancer and treatments. Median age was 54 years (yrs) (range 25-91). Median time between initial diagnosis (dx) of breast cancer and MBC was 2 yrs; 424 pts were dx’d with de novo MBC. 1022 (87%) reported having a biopsy at or following their dx of MBC. Median time since MBC dx was 3 yrs; 87 reported having MBC >10 yrs. 436 (37%) reported being on a therapy for >2 yrs; 672 (57%) reported an “extraordinary response” to a therapy. For example, 77 reported long and/or extraordinary responses to capecitabine ; 44 to platinums, and 20 to everolimus. Initial medical records, saliva, and tumors have been received. Conclusions: A direct-to-patient approach enabled rapid identification of large numbers of MBC pts willing to share tumors, saliva, and medical records. This includes many with rare phenotypes, a group that has been challenging to identify with traditional approaches. Genomic analysis of pts with extraordinary responses and with de novo MBC are underway. Pt reported data has also identified unanticipated research questions.

18 New method of assessing tumor heterogeneity utilizing both circulating tumor DNA and tissue DNA to predict the response to immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A18-A18
Author(s):  
Jaeyoun Choi ◽  
Myungwoo Nam ◽  
Stanislav Fridland ◽  
Jinyoung Hwang ◽  
Chan Mi Jung ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Response ◽  
Allele Frequency ◽  
Scoring System ◽  
Tumor Heterogeneity ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
List Type ◽  
Multiple Biopsies ◽  
Tumor Dna

BackgroundTumor heterogeneity assessment may help predict response to immunotherapy. In melanoma mouse models, tumor heterogeneity impaired immune response.1 In addition, among lung cancer patients receiving immunotherapy, the high clonal neoantigen group had favorable survival and outcomes.2 Ideal methods of quantifying tumor heterogeneity are multiple biopsies or autopsy. However, these are not feasible in routine clinical practice. Circulating tumor DNA (ctDNA) is emerging as an alternative. Here, we reviewed the current state of tumor heterogeneity quantification from ctDNA. Furthermore, we propose a new tumor heterogeneity index(THI) based on our own scoring system, utilizing both ctDNA and tissue DNA.MethodsSystematic literature search on Pubmed was conducted up to August 18, 2020. A scoring system and THI were theoretically derived.ResultsTwo studies suggested their own methods of assessing tumor heterogeneity. One suggested clustering mutations with Pyclone,3 and the other suggested using the ratio of allele frequency (AF) to the maximum somatic allele frequency (MSAF).4 According to the former, the mutations in the highest cellular prevalence cluster can be defined as clonal mutations. According to the latter, the mutations with AF/MSAF<10% can be defined as subclonal mutations. To date, there have been no studies on utilizing both ctDNA and tissue DNA simultaneously to quantify tumor heterogeneity. We hypothesize that a mutation found in only one of either ctDNA or tissue DNA has a higher chance of being subclonal.We suggest a scoring system based on the previously mentioned methods to estimate the probability for a mutant allele to be subclonal. Adding up the points that correspond to the conditions results in a subclonality score (table 1). In a given ctDNA, the number of alleles with a subclonality score greater than or equal to 2 divided by the total number of alleles is defined as blood THI (bTHI) (figure 1). We can repeat the same calculation in a given tissue DNA for tissue THI (tTHI) (figure 2). Finally, we define composite THI (cTHI) as the mean of bTHI and tTHI.Abstract 18 Table 1Subclonality scoreAbstract 18 Figure 1Hypothetical distribution of all alleles found in ctDNA bTHI = the number of alleles with a subclonality score greater than or equal to 2/the total number of alleles found in ctDNA = 10/20 =50%Abstract 18 Figure 2Hypothetical distribution of all alleles found in tissue DNA tTHI= the number of alleles with a subclonality score greater than or equal to 2/the total number of alleles found in tissue DNA = 16/40 = 40% cTHI= (bTHI + tTHI)/2 = 45%ConclusionsTumor heterogeneity is becoming an important biomarker for predicting response to immunotherapy. Because autopsy and multiple biopsies are not feasible, utilizing both ctDNA and tissue DNA is the most comprehensive and practical approach. Therefore, we propose cTHI, for the first time, as a quantification measure of tumor heterogeneity.ReferencesWolf Y, Bartok O. UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma. Cell 2019;179:219–235.McGranahan N, Swanton C. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463–1469.Ma F, Guan Y. Assessing tumor heterogeneity using ctDNA to predict and monitor therapeutic response in metastatic breast cancer. Int J Cancer 2020;146:1359–1368.Liu Z, Xie Z. Presence of allele frequency heterogeneity defined by ctDNA profiling predicts unfavorable overall survival of NSCLC. Transl Lung Cancer Res 2019;8:1045–1050.

scholarly journals Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gillian Vandekerkhove ◽  
Jean-Michel Lavoie ◽  
Matti Annala ◽  
Andrew J. Murtha ◽  
Nora Sundahl ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Treatment Options ◽  
Circulating Tumor Dna ◽  
Molecular Stratification ◽  
Clinical Biomarkers ◽  
Surgery Patient ◽  
Metastatic Urothelial Carcinoma ◽  
Ctdna Analysis ◽  
Clinical Genomic ◽  
Tumor Dna

AbstractMolecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.

scholarly journals Combining tissue and circulating tumor DNA increases the detection rate of a CTNNB1 mutation in hepatocellular carcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Stine Karlsen Oversoe ◽  
Michelle Simone Clement ◽  
Britta Weber ◽  
Henning Grønbæk ◽  
Stephen Jacques Hamilton-Dutoit ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mutation Rate ◽  
Detection Rate ◽  
Tumor Tissue ◽  
Circulating Tumor Dna ◽  
Treatment Modalities ◽  
Advanced Hepatocellular Carcinoma ◽  
Tissue Samples ◽  
The Impact ◽  
Tumor Dna

Abstract Background and aims Studies suggest that mutations in the CTNNB1 gene are predictive of response to immunotherapy, an emerging therapy for advanced hepatocellular carcinoma (HCC). Analysis of circulating tumor DNA (ctDNA) offers the possibility of serial non-invasive mutational profiling of tumors. Combining tumor tissue and ctDNA analysis may increase the detection rate of mutations. This study aimed to evaluate the frequency of the CTNNB1 p.T41A mutation in ctDNA and tumor samples from HCC patients and to evaluate the concordance rates between plasma and tissue. We further evaluated changes in ctDNA after various HCC treatment modalities and the impact of the CTNNB1 p.T41A mutation on the clinical course of HCC. Methods We used droplet digital PCR to analyze plasma from 95 patients and the corresponding tumor samples from 37 patients during 3 years follow up. Results In tumor tissue samples, the mutation rate was 8.1% (3/37). In ctDNA from HCC patients, the CTNNB1 mutation rate was 9.5% (9/95) in the pre-treatment samples. Adding results from plasma analysis to the subgroup of patients with available tissue samples, the mutation detection rate increased to 13.5% (5/37). There was no difference in overall survival according to CTNNB1 mutational status. Serial testing of ctDNA suggested a possible clonal evolution of HCC or arising multicentric tumors with separate genetic profiles in individual patients. Conclusion Combining analysis of ctDNA and tumor tissue increased the detection rate of CTNNB1 mutation in HCC patients. A liquid biopsy approach may be useful in a tailored therapy of HCC.

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