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   Table of Contents - Current issue
October-December 2019
Volume 2 | Issue 4
Page Nos. 127-175

Online since Monday, November 11, 2019

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Cancer immunotherapy in the immunosuppressed patients and its relevance to clinical practice p. 127
Vaia Florou, Ignacio Garrido-Laguna
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In the era of immune checkpoint inhibitor therapy, can we safely expand to patients with immunodeficiency? p. 129
Mehmet Asim Bilen, Razelle Kurzrock
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Analysis of Programmed Death-Ligand 1 Expression, Stromal Tumor-Infiltrating Lymphocytes, and Mismatch Repair Deficiency in Invasive Micropapillary Carcinoma of the Breast p. 130
Sara Simonetti, Nuria Dominguez, Analia Elguezabal, Francesco Pepe, Mariantonia Nacchio, Floriana Conticelli, Umberto Malapelle, Giancarlo Troncone, Lidia Sanchez, Xavier Guardia, Paolo Nuciforo, Luigi Insabato
Introduction: Invasive micropapillary carcinoma(IMPC) of the breast is a rare and aggressive subtype of invasive ductal carcinomas, associated with poor prognosis and without a well-established treatment. Programmed death-ligand 1(PD-L1) expression, high tumor-infiltrating lymphocytes(TILs), and microsatellite instability have recently been linked to susceptibility to immunotherapies against PD-1/PD-L1 axis. No exhaustive data is available on the status of these predictive markers in IMPCs of the breast. The aim of our study is to analyze PD-L1 expression, stromal TIL(sTIL), and mismatch repair(MMR) gene status in IMPCs of the breast, to extend the therapeutic possibilities of these rare aggressive tumors. Materials and Methods: Thirty-seven cases of IMPCs diagnosed in two European institutions between 2003 and 2017 with detailed clinical and pathologic data were analyzed. sTILs were assessed in hematoxylin and eosin-stained sections. MMR deficiency was tested by either immunohistochemistry(IHC) for MMR proteins(MLH1, MSH2, MSH6, and PMS2) or capillary electrophoresis for microsatellite instability using a standardized panel of five loci(Bat25, Bat26, D2S123, D5S346, and D17S250). For PD-L1, expression in both tumor cells(TCs) and immune cells(ICs) was determined using the antibody clone SP263. Results: The median sTILs was 3%(mean: 6%, range: 0–40). Thirty-one cases(84%) showed≤10% of sTILs and only one case had 40% of sTILs. Higher median TILs were more frequently observed in lymph node metastases. PD-L1 expression(≥1%) was observed in 4(11%) and 14(38%) cases in TCs and ICs, respectively. None of the tumors showed PD-L1 expression in>1% of TCs. Only three cases showed expression in>10% of ICs. All cases were microsatellite stable by either IHC or polymerase chain reaction analyses. Conclusions: IMPCs of the breast are microsatellite-stable and immune desert tumors with low PD-L1 expression, thus arguing against the use of immune-checkpoint inhibitors in these patients. Active immunotherapy strategies attempting to stimulate self-immune system to attack tumor are needed.
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Haplotype Analysis of the T-Cell Receptor Beta (TCRB) Locus by Long-amplicon TCRB Repertoire Sequencing p. 137
Timothy J Looney, Dzifa Y Duose, Geoffrey Lowman, Elizabeth Linch, Joud Hajjar, Denise Topacio-Hall, Mingxuan Xu, Jianping Zheng, Anas Alshawa, Coya Tapia, Bettzy Stephen, Linghua Wang, Funda Meric-Bernstam, Lauren Miller, Alexander Glavin, Lifeng Lin, Jing Gong, Jeffrey Conroy, Carl Morrison, Fiona Hyland, Aung Naing
Background: Polymorphism within the human T-cell receptor beta variable (TRBV) gene has been proposed as a risk factor for autoimmune disease and immune-related adverse events (IRAEs) during immunotherapy. Previous efforts to evaluate TRBV polymorphism by whole genome sequencing have been hampered by the repetitive nature of the T-cell receptor beta (TCRB) locus. We present a novel long-amplicon TCRB repertoire sequencing approach to enable TRBV haplotype analysis from peripheral blood. Methods: Peripheral blood leukocyte total RNA from 81 Caucasians was used for sequencing of TCRB chains via the Oncomine TCRB-LR assay (amplicon spanning CDR1, 2 and 3) and the Ion Gene Studio S5. VDJ rearrangements were annotated by comparison to the IMGT database, then mined to construct TRBV allele profiles for each individual including, where detected, novel alleles not present in the ImMunoGeneTics (IMGT) database. Finally, TRBV allele profiles were subjected to principal component analysis and k-means clustering to identify TRBV allele haplotypes. Results: Clustering analysis revealed the presence of six major sets of coincident TRBV alleles, which we term haplotype groups. Allelic diversity varied markedly across haplotype groups, with approximately one third of the cohort showing limited TRBV allelic diversity and few uncommon alleles compared to members of other groups. Analysis revealed 37 putatively novel TRBV alleles that are absent from the IMGT database. Conclusion: We demonstrate a straightforward and cost-efficient method for TRBV haplotype analysis from long-amplicon TCRB sequencing data.
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Review of immunogenomics and the role of tumor mutational burden as a biomarker for immunotherapy response p. 144
Javier Ros, Iosune Baraibar, Ana Vivancos, Jordi Rodon
Immune checkpoint inhibitors benefit a proportion of patients with cancer, but not all patients nor all histologies will respond to immunotherapy. Therefore, predictive biomarkers are needed. In this review, we outline the ways that lead to hypermutated tumors as well as the potential predictive role of tumor mutational burden (TMB). Findings in selected cancer types suggest that TMB may predict clinical response to immunotherapy, and recently even a prognostic role has been suggested for TMB. An association between high mutational load and clinical benefit was observed in various tumor types; however, it is unclear whether TMB is a strong predictive marker of clinical benefit across all cancers. For that reason, there are still several questions regarding the role of TMB as an immunotherapy biomarker, such as the best measurement technique, the most adequate cutoff, or even whether TMB will be useful for any kind of cancer. We have performed an extensive bibliography research using PubMed with keys words: immunotherapy, tumor mutational load, TMB, immunotherapy biomarkers, and immunotherapy response. In conclusion, TMB has been demonstrated to be a useful biomarker for immunotherapy selection across some cancer types; however, further validation studies are required.
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MET receptor amplification drives resistance to Anti-EGFR therapies p. 152
Patricia Martin Romano, Eduardo Castanon, Antoine Hollebecque, Ludovic Lacroix, Nathalie Auger, Eric Angevin, Lambros Tselikas, Sami Ammari, Jean-Charles Soria, Christophe Massard
Mesenchymal–epithelial transition factor (MET) amplification has been suggested either as a de novo or acquired mechanism of resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy. However, even if MET amplification has been widely described in the preclinical setting, only a few clinical data have confirmed the role of MET in the resistance to anti-EGFR treatment. A 60-year-old man presenting cholangiocarcinoma with EGFR amplification had a tumor response to anti-EGFR therapy. A new on-purpose tumor biopsy performed during tumor progression confirmed the known EGFR amplification as well as a new MET amplification. This clinical observation highlights the role of MET amplification as a mechanism of resistance to EGFR inhibitors.
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Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK: Meeting Overview p. 156
Donna M Graham, Louise Carter, Matthew G Krebs, Duncan Jodrell, Anne Armstrong, Elaine Kilgour, Tim Illidge, Joseph Clarke, Rachel Chown, Kaye Williams, Caroline Dive, Janelle Yorke, Clare Dickinson, Andrew Hughes, Fiona Thistlethwaite, Rob Bristow, Natalie Cook
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Guest Editor and Reviewer Acknowledgments p. 175

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