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

Bradley A. Hancock, Yu Hsiang Chen, Jeffrey P. Solzak, Mufti N. Ahmad, David C. Wedge, Dumitru Brinza, Charles Scafe, James Veitch, Rajesh Gottimukkala, Walt Short, Rutuja V. Atale, Mircea Ivan, Sunil Badve, Bryan Schneider, Xiongbin Lu, Kathy Miller, Milan Radovich

Research output: Contribution to journalArticle

Abstract

Background: Approximately 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. Methods: We 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. Results: Analysis 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. Conclusions: We 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.

Original languageEnglish (US)
Article number87
JournalBreast Cancer Research
Volume21
Issue number1
DOIs
StatePublished - Aug 5 2019

Fingerprint

Triple Negative Breast Neoplasms
Recurrence
Drug Therapy
Residual Neoplasm
Mutation
Clonal Evolution
RNA Sequence Analysis
Biopsy
Gene Expression
Kaplan-Meier Estimate
Survival Analysis
Transducers
DNA Sequence Analysis
Oncogenes
Point Mutation
Neoplasms
Up-Regulation
Stem Cells
Therapeutics
Clinical Trials

Keywords

  • Breast
  • Cancer
  • Chemoresistance
  • MYC
  • Recurrence
  • Relapse
  • SMAD2
  • TGF-beta
  • TP53
  • Triple-negative

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Profiling molecular regulators of recurrence in chemorefractory triple-negative breast cancers. / Hancock, Bradley A.; Chen, Yu Hsiang; Solzak, Jeffrey P.; Ahmad, Mufti N.; Wedge, David C.; Brinza, Dumitru; Scafe, Charles; Veitch, James; Gottimukkala, Rajesh; Short, Walt; Atale, Rutuja V.; Ivan, Mircea; Badve, Sunil; Schneider, Bryan; Lu, Xiongbin; Miller, Kathy; Radovich, Milan.

In: Breast Cancer Research, Vol. 21, No. 1, 87, 05.08.2019.

Research output: Contribution to journalArticle

Hancock, BA, Chen, YH, Solzak, JP, Ahmad, MN, Wedge, DC, Brinza, D, Scafe, C, Veitch, J, Gottimukkala, R, Short, W, Atale, RV, Ivan, M, Badve, S, Schneider, B, Lu, X, Miller, K & Radovich, M 2019, 'Profiling molecular regulators of recurrence in chemorefractory triple-negative breast cancers', Breast Cancer Research, vol. 21, no. 1, 87. https://doi.org/10.1186/s13058-019-1171-7
Hancock, Bradley A. ; Chen, Yu Hsiang ; Solzak, Jeffrey P. ; Ahmad, Mufti N. ; Wedge, David C. ; Brinza, Dumitru ; Scafe, Charles ; Veitch, James ; Gottimukkala, Rajesh ; Short, Walt ; Atale, Rutuja V. ; Ivan, Mircea ; Badve, Sunil ; Schneider, Bryan ; Lu, Xiongbin ; Miller, Kathy ; Radovich, Milan. / Profiling molecular regulators of recurrence in chemorefractory triple-negative breast cancers. In: Breast Cancer Research. 2019 ; Vol. 21, No. 1.
@article{1c5fea8c778b40f78234e390a7b157d1,
title = "Profiling molecular regulators of recurrence in chemorefractory triple-negative breast cancers",
abstract = "Background: Approximately 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. Methods: We 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. Results: Analysis 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 TGF{\ss} signaling through the signal transducer SMAD2. Conclusions: We 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 TGF{\ss} signaling in RD samples are prominent drivers of recurrence, representing high-yield targets for additional interrogation.",
keywords = "Breast, Cancer, Chemoresistance, MYC, Recurrence, Relapse, SMAD2, TGF-beta, TP53, Triple-negative",
author = "Hancock, {Bradley A.} and Chen, {Yu Hsiang} and Solzak, {Jeffrey P.} and Ahmad, {Mufti N.} and Wedge, {David C.} and Dumitru Brinza and Charles Scafe and James Veitch and Rajesh Gottimukkala and Walt Short and Atale, {Rutuja V.} and Mircea Ivan and Sunil Badve and Bryan Schneider and Xiongbin Lu and Kathy Miller and Milan Radovich",
year = "2019",
month = "8",
day = "5",
doi = "10.1186/s13058-019-1171-7",
language = "English (US)",
volume = "21",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Profiling molecular regulators of recurrence in chemorefractory triple-negative breast cancers

AU - Hancock, Bradley A.

AU - Chen, Yu Hsiang

AU - Solzak, Jeffrey P.

AU - Ahmad, Mufti N.

AU - Wedge, David C.

AU - Brinza, Dumitru

AU - Scafe, Charles

AU - Veitch, James

AU - Gottimukkala, Rajesh

AU - Short, Walt

AU - Atale, Rutuja V.

AU - Ivan, Mircea

AU - Badve, Sunil

AU - Schneider, Bryan

AU - Lu, Xiongbin

AU - Miller, Kathy

AU - Radovich, Milan

PY - 2019/8/5

Y1 - 2019/8/5

N2 - Background: Approximately 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. Methods: We 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. Results: Analysis 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. Conclusions: We 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.

AB - Background: Approximately 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. Methods: We 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. Results: Analysis 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. Conclusions: We 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.

KW - Breast

KW - Cancer

KW - Chemoresistance

KW - MYC

KW - Recurrence

KW - Relapse

KW - SMAD2

KW - TGF-beta

KW - TP53

KW - Triple-negative

UR - http://www.scopus.com/inward/record.url?scp=85070336730&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070336730&partnerID=8YFLogxK

U2 - 10.1186/s13058-019-1171-7

DO - 10.1186/s13058-019-1171-7

M3 - Article

C2 - 31383035

AN - SCOPUS:85070336730

VL - 21

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

M1 - 87

ER -