Samuel S. Freeman

Broad Institute

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Gad Getz

Broad Institute

108

Nikhil Wagle

Harvard University

Gavin Ha

Brotman Baty Institute

Viktor A. Adalsteinsson

Broad Institute

Nancy U. Lin

Harvard University

Ofir Cohen

Ben-Gurion University of the Negev

Eric P. Winer

Dana-Farber Cancer Institute

Matthew Meyerson

Harvard University

Justin Rhoades

Broad Institute

Pedro Exman

Instituto do Câncer do Estado de São Paulo

Cooperative Institutions

Harvard University

613

Dana-Farber Cancer Institute

457

Broad Institute

424

Massachusetts Institute of Technology

271

Brigham and Women's Hospital

258

Massachusetts General Hospital

253

National Institutes of Health

196

University of Birmingham

194

The University of Texas MD Anderson Cancer Center

168

Memorial Sloan Kettering Cancer Center

154

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Justice and the Social Contract

Samuel S. Freeman

Abstract John Rawls (1921-2002) was one of the 20th century's most important philosophers and continues to be among the most widely discussed of contemporary thinkers. His work, particularly A Theory of Justice, is integral to discussions of social and international justice, democracy, liberalism, welfare economics, and constitutional law, in departments of philosophy, politics, economics, law, public policy, and others. Samuel Freeman is one of Rawls's foremost interpreters. This volume contains nine of his essays on Rawls and Rawlsian justice, two of which are previously unpublished. Freeman places Rawls within historical context in the social contract tradition, addresses criticisms of his positions, and discusses the implications of his views on issues of distributive justice, liberalism and democracy, international justice, and other subjects. This collection will be useful to the wide range of scholars interested in Rawls and theories of justice.

Classical liberalism

Social Contract

Primary goods

10.1093/oso/9780195301410.001.0001

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Citations (182)

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer

Clinical Cancer Research (2020)

Heather A. Parsons Justin Rhoades Sarah C. Reed Gregory Gydush Priyanka Ram

Abstract Purpose: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing. Experimental Design: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2− metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples. Results: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2–346). Clinical sensitivity was 81% (n = 13/16) in newly diagnosed MBC, 23% (n = 7/30) at postoperative and 19% (n = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3–58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4–39.2 months). Conclusions: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.

Minimal Residual Disease

10.1158/1078-0432.ccr-19-3005

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Implementation of a prostate cancer‐specific targeted sequencing panel for credentialing of patient‐derived cell lines and genomic characterization of patient samples

The Prostate (2022)

Elizabeth H. Stover Coyin Oh Paula Keskula Atish D. Choudhury Yuen‐Yi Tseng

Abstract Background Primary and metastatic prostate cancers have low mutation rates and recurrent alterations in a small set of genes, enabling targeted sequencing of prostate cancer‐associated genes as an efficient approach to characterizing patient samples (compared to whole‐exome and whole‐genome sequencing). For example, targeted sequencing provides a flexible, rapid, and cost‐effective method for genomic assessment of patient‐derived cell lines to evaluate fidelity to initial patient tumor samples. Methods We developed a prostate cancer‐specific targeted next‐generation sequencing (NGS) panel to detect alterations in 62 prostate cancer‐associated genes as well as recurring gene fusions with ETS family members, representing the majority of common alterations in prostate cancer. We tested this panel on primary prostate cancer tissues and blood biopsies from patients with metastatic prostate cancer. We generated patient‐derived cell lines from primary prostate cancers using conditional reprogramming methods and applied targeted sequencing to evaluate the fidelity of these cell lines to the original patient tumors. Results The prostate cancer‐specific panel identified biologically and clinically relevant alterations, including point mutations in driver oncogenes and ETS family fusion genes, in tumor tissues from 29 radical prostatectomy samples. The targeted panel also identified genomic alterations in cell‐free DNA and circulating tumor cells (CTCs) from patients with metastatic prostate cancer, and in standard prostate cancer cell lines. We used the targeted panel to sequence our set of patient‐derived cell lines; however, no prostate cancer‐specific mutations were identified in the tumor‐derived cell lines, suggesting preferential outgrowth of normal prostate epithelial cells. Conclusions We evaluated a prostate cancer‐specific targeted NGS panel to detect common and clinically relevant alterations (including ETS family gene fusions) in prostate cancer. The panel detected driver mutations in a diverse set of clinical samples of prostate cancer, including fresh‐frozen tumors, cell‐free DNA, CTCs, and cell lines. Targeted sequencing of patient‐derived cell lines highlights the challenge of deriving cell lines from primary prostate cancers and the importance of genomic characterization to credential candidate cell lines. Our study supports that a prostate cancer‐specific targeted sequencing panel provides an efficient, clinically feasible approach to identify genetic alterations across a spectrum of prostate cancer samples and cell lines.

Chromoplexy

10.1002/pros.24305

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Citations (2)

The Cancer Genome Atlas Expression Subtypes Stratify Response to Checkpoint Inhibition in Advanced Urothelial Cancer and Identify a Subset of Patients with High Survival Probability

European Urology (2019)

Jaegil Kim David J. Kwiatkowski David J. McConkey Joshua J. Meeks Samuel S. Freeman

Atezolizumab

Immune checkpoint

Personalized Medicine

10.1016/j.eururo.2019.02.017

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Citations (161)

Supplemental Table 3 from Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer

Pingping Mao Ofir Cohen Kailey J. Kowalski Justin G. Kusiel Jorge E. Buendia-Buendia

FGFR alterations in different cohorts

10.1158/1078-0432.22476827

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Supplementary Tables from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer

Heather A. Parsons Justin Rhoades Sarah C. Reed Gregory Gydush Priyanka Ram

Supplementary Tables

Minimal Residual Disease

10.1158/1078-0432.22478900.v1

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Supplementary Figure 3 from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer

Heather A. Parsons Justin Rhoades Sarah C. Reed Gregory Gydush Priyanka Ram

Overview schematic of MRD assay. MRD assay workflow from characterizing a primary tumor to determining if a blood draw contains evidence of residual disease.

Minimal Residual Disease

10.1158/1078-0432.22478924.v1

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Supplementary Figure 13 from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer

Heather A. Parsons Justin Rhoades Sarah C. Reed Gregory Gydush Priyanka Ram

Patients who were recurrence free after treatment for early stage breast cancer. cfDNA time points for all patients who did not experienced recurrence. Those marked with poor detection limits had an estimated detection limit worse than 1/1,000. End points represent time of last follow up or death.

10.1158/1078-0432.22478939.v1

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Supplementary Data from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer

Heather A. Parsons Justin Rhoades Sarah C. Reed Gregory Gydush Priyanka Ram

Supplementary Methods

Minimal Residual Disease

10.1158/1078-0432.22478954.v1

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Supplementary Figure 15 from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer

Heather A. Parsons Justin Rhoades Sarah C. Reed Gregory Gydush Priyanka Ram

MRD testing results in early stage breast cancer cohort. (A) Detection limits versus the number of SNVs tracked for each cfDNA sample. (B) Comparison of fingerprint size distributions between patients that were MRD+ at any time point and those that were always MRD-, split by distant recurrence status. The Mann-Whitney U test was used to determine whether MRD+ patients tracked significantly more mutations than MRD- patients. (C) Tumor fractions for MRD+ samples from patients with distant recurrence split by the minimum fingerprint size required to still detect MRD.

Minimal Residual Disease

10.1158/1078-0432.22478933.v1

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