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Profiling molecular regulators of recurrence in chemorefractory triple-negative breast cancers

Authors
  • Hancock, Bradley A.1
  • Chen, Yu-Hsiang2
  • Solzak, Jeffrey P.1
  • Ahmad, Mufti N.1
  • Wedge, David C.3
  • Brinza, Dumitru4
  • Scafe, Charles4
  • Veitch, James4
  • Gottimukkala, Rajesh4
  • Short, Walt4
  • Atale, Rutuja V.1
  • Ivan, Mircea5
  • Badve, Sunil S.6, 7
  • Schneider, Bryan P.2, 8, 7
  • Lu, Xiongbin2, 7
  • Miller, Kathy D.8, 7
  • Radovich, Milan1, 2, 7, 9
  • 1 Indiana University School of Medicine, Department of Surgery, 980 W. Walnut St. Room C312, Indianapolis, IN, 46202, USA , Indianapolis (United States)
  • 2 Indiana University School of Medicine, Department of Medical & Molecular Genetics, Indianapolis, IN, 46202, USA , Indianapolis (United States)
  • 3 Li Ka Shing Centre for Health Information and Discovery, Big Data Institute, Oxford, UK , Oxford (United Kingdom)
  • 4 ThermoFisher Scientific, Department of Bioinformatics, Carlsbad, CA, USA , Carlsbad (United States)
  • 5 Indiana University School of Medicine, Department of Microbiology and Immunology, Indianapolis, IN, 46202, USA , Indianapolis (United States)
  • 6 Indiana University School of Medicine, Department of Pathology and Laboratory Medicine, Indianapolis, IN, 46202, USA , Indianapolis (United States)
  • 7 Indiana University School of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA , Indianapolis (United States)
  • 8 Indiana University School of Medicine, Division of Hematology/Oncology, Department of Medicine, Indianapolis, IN, 46202, USA , Indianapolis (United States)
  • 9 Indiana University School of Medicine, Indiana University Center for Computational Biology and Bioinformatics, Indianapolis, IN, 46202, USA , Indianapolis (United States)
Type
Published Article
Journal
Breast Cancer Research
Publisher
BioMed Central
Publication Date
Aug 05, 2019
Volume
21
Issue
1
Identifiers
DOI: 10.1186/s13058-019-1171-7
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundApproximately two thirds of patients with localized triple-negative breast cancer (TNBC) harbor residual disease (RD) after neoadjuvant chemotherapy (NAC) and have a high risk-of-recurrence. Targeted therapeutic development for TNBC is of primary significance as no targeted therapies are clinically indicated for this aggressive subset. In view of this, we conducted a comprehensive molecular analysis and correlated molecular features of chemorefractory RD tumors with recurrence for the purpose of guiding downstream therapeutic development.MethodsWe assembled DNA and RNA sequencing data from RD tumors as well as pre-operative biopsies, lymphocytic infiltrate, and survival data as part of a molecular correlative to a phase II post-neoadjuvant clinical trial. Matched somatic mutation, gene expression, and lymphocytic infiltrate were assessed before and after chemotherapy to understand how tumors evolve during chemotherapy. Kaplan-Meier survival analyses were conducted categorizing cancers with TP53 mutations by the degree of loss as well as by the copy number of a locus of 18q corresponding to the SMAD2, SMAD4, and SMAD7 genes.ResultsAnalysis of matched somatic genomes pre-/post-NAC revealed chaotic acquisition of copy gains and losses including amplification of prominent oncogenes. In contrast, significant gains in deleterious point mutations and insertion/deletions were not observed. No trends between clonal evolution and recurrence were identified. Gene expression data from paired biopsies revealed enrichment of actionable regulators of stem cell-like behavior and depletion of immune signaling, which was corroborated by total lymphocytic infiltrate, but was not associated with recurrence. Novel characterization of TP53 mutation revealed prognostically relevant subgroups, which were linked to MYC-driven transcriptional amplification. Finally, somatic gains in 18q were associated with poor prognosis, likely driven by putative upregulation of TGFß signaling through the signal transducer SMAD2.ConclusionsWe conclude TNBCs are dynamic during chemotherapy, demonstrating complex plasticity in subclonal diversity, stem-like qualities, and immune depletion, but somatic alterations of TP53/MYC and TGFß signaling in RD samples are prominent drivers of recurrence, representing high-yield targets for additional interrogation.

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