You will synthesize the three research articles (submitted in week 4) about your topic discussed in Modules 1 & 2. A synthesis includes an analysis of the aggregate of articles, not the individual articles. e.g. clustering and interrelating ideas from the studies to form an overall representation of the conceptual definitions, descriptions, interventions, instruments, and strengths and weaknesses of the body of knowledge represented by the articles. You should have citations to support all three articles in this synthesis. See the examples in Chapter 7 (in particular, Synthesizing Sources) and Chapter 18 related to Quantitative Research in Gray & Grove (2021). This is a discussion, not a paper! Be succinct and include the questions below.
Use the following questions to synthesize your three articles:
1. What are the conclusions drawn from the articles in relation to your topic?
2. Identify similarities and differences of the studies. These may include a discussion of the samples, research designs, and findings, for example.
3. Are there conflicting findings among the articles?
Research
JAMA Oncology | Original Investigation
Analysis of the Prevalence of Microsatellite Instability
in Prostate Cancer and Response
to Immune Checkpoint Blockade
Wassim Abida, MD, PhD; Michael L. Cheng, MD; Joshua Armenia, PhD; Sumit Middha, PhD; Karen A. Autio, MD;
Hebert Alberto Vargas, MD; Dana Rathkopf, MD; Michael J. Morris, MD; Daniel C. Danila, MD;
Susan F. Slovin, MD, PhD; Emily Carbone, BA; Ethan S. Barnett, MS; Melanie Hullings, BA; Jaclyn F. Hechtman, MD;
Ahmet Zehir, PhD; Jinru Shia, MD; Philip Jonsson, PhD; Zsofia K. Stadler, MD; Preethi Srinivasan, BA;
Vincent P. Laudone, MD; Victor Reuter, MD; Jedd D. Wolchok, MD, PhD; Nicholas D. Socci, PhD;
Barry S. Taylor, PhD; Michael F. Berger, PhD; Philip W. Kantoff, MD; Charles L. Sawyers, MD;
Nikolaus Schultz, PhD; David B. Solit, MD; Anuradha Gopalan, MD; Howard I. Scher, MD
Invited Commentary page 478
IMPORTANCE The anti–programmed cell death protein 1 (PD-1) antibody pembrolizumab is
Supplemental content
approved by the US Food and Drug Administration for the treatment of microsatellite
instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors, but the
prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint
blockade in this disease subset are unknown.
OBJECTIVE To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit
of anti–PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined
population.
DESIGN, SETTING, AND PARTICIPANTS In this case series, 1551 tumors from 1346 patients
with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center
were prospectively analyzed using a targeted sequencing assay from January 1, 2015,
through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to
tumor molecular profiling when a tumor biopsy was planned or archival tissue was available.
For each patient, clinical outcomes were reported, with follow-up until May 31, 2018.
MAIN OUTCOMES AND MEASURES Tumor mutation burden and MSIsensor score, a
quantitative measure of MSI, were calculated. Mutational signature analysis and
immunohistochemistry for MMR protein expression were performed in select cases.
RESULTS Among the 1033 patients who had adequate tumor quality for MSIsensor analysis
(mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three
of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had
indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/dMMR patients (21.9%)
had a pathogenic germline mutation in a Lynch syndrome–associated gene. Six patients had
more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their
disease course. Eleven patients with MSI-H/dMMR castration-resistant prostate cancer
received anti–PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in
prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018,
5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks.
CONCLUSIONS AND RELEVANCE The MSI-H/dMMR molecular phenotype is uncommon yet
therapeutically meaningful in prostate cancer and can be somatically acquired during disease
evolution. Given the potential for durable responses to anti–PD-1/PD-L1 therapy, these
findings support the use of prospective tumor sequencing to screen all patients with
advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/dMMR
phenotype respond, further studies should explore mechanisms of resistance.
JAMA Oncol. 2019;5(4):471-478. doi:10.1001/jamaoncol.2018.5801
Published online December 27, 2018.
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Wassim
Abida, MD, PhD, Department of
Medicine, Memorial Sloan Kettering
Cancer Center, 1275 York Ave,
New York, NY 10065
(abidam@mskcc.org).
(Reprinted) 471
© 2018 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 04/27/2023
Research Original Investigation
Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade
I
mmune checkpoint blockade has shown limited benefit in
prostate cancer in several studies.1-3 Nonetheless, durable
objective responses have been reported, suggesting that patients with molecularly defined subsets of prostate cancer may
benefit from this therapeutic approach.4-6 Pembrolizumab, an
antibody targeting the programmed cell death protein 1 (PD-1)
receptor, recently earned accelerated approval by the US Food
and Drug Administration for the treatment of microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR)
solid tumors, independent of site of origin. Detection of MSI
thus represents the first clinical indication for prospective tumor profiling in patients with prostate cancer.7 However, the
optimal method for determining MSI-H/dMMR status in patients with prostate cancer and the clinical implications of
broader screening for this phenotype remain unknown.
The prevalence of MSI-H/dMMR prostate cancer is unclear, with frequencies ranging from 1.2% to 12.0% in prior
reports.8,9 Recent sequencing studies of metastatic castration–
resistant prostate cancer (mCRPC) showed that 2% to 3% of tumors have a higher mutation burden that is often associated
with genomic alterations in MMR-associated genes, suggesting that tumor sequencing may be an efficient method for identifying MSI-H/dMMR prostate cancer.10,11 Herein, we leveraged a prospectively generated genomic data set of 1551
prostate tumors from 1346 patients to define the frequency of
MSI-H/dMMR prostate cancer and report outcomes for patients with MSI-H/dMMR mCRPC who were treated with anti–
PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy.
Key Points
Question What is the prevalence of microsatellite instability in
prostate cancer and its association with response to immune
checkpoint blockade?
Findings In this case series of 1346 patients with prostate cancer
who underwent paired tumor and germline sequencing, 32 of 1033
(3.1%) had microsatellite instability–high or mismatch repair
deficient disease, of whom 7 (21.9%) carried a germline mutation
in a Lynch syndrome–associated gene. Five of 11 patients who
received an anti–PD-1/PD-L1 agent had durable clinical benefit.
Meaning The microsatellite instability–high/mismatch repair
deficient phenotype is uncommon but clinically important in
prostate cancer and can be somatically acquired during disease
evolution.
on pathologic review) were flagged, and their MSIsensor
scores were excluded from the primary analysis. Tumor
mutation burden (TMB) was calculated as mutations per
megabase (mut/Mb). Mutational signature analysis 16,17
(eMethods in the Supplement) was performed for tumors
with somatic mutation counts of at least 10. Alterations in
MMR genes were considered deleterious and likely oncogenic if they were pathogenic or likely pathogenic alterations
present in the germline18,19 or if they were somatic truncating mutations or deletions.20 For statistical analysis, comparison of MSI-H/dMMR frequency between disease subsets
was performed using a 2-tailed Fisher exact text.
Methods
Results
Patients and Samples
From January 1, 2015, through January 31, 2018, 1551 tumors
from 1346 patients with prostate cancer treated at Memorial
Sloan Kettering Cancer Center, New York, New York, underwent clinical genomic profiling with a hybridization capture–
based next-generation sequencing assay (Integrated Mutation
Profiling of Actionable Cancer Targets [MSK-IMPACT]).12,13 Patients were given the option to consent to secondary germline
analysis. Immunohistochemical (IHC) analysis for MSH2 (OMIM
609309), MSH6 (OMIM 600678), MLH1 (OMIM 600678), and
PMS2 (OMIM 600259) was performed on select tumors. Medical record review for patient clinical characteristics and outcomes, with follow-up until May 31, 2018, was performed under a protocol approved by the institutional review board of
Memorial Sloan Kettering Cancer Center, with a waiver of consent for the analysis of deidentified data.
Sequencing and Analysis
Tumors and matched normal blood samples were sequenced
as previously described.10,13 An algorithm for the detection
of somatic microsatellite changes using paired tumornormal sequence data (MSIsensor)14,15 was applied to all
tumors, yielding a quantitative MSIsensor score. Tumors
deemed to have inadequate tumor content or quality
(
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