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NPJ Breast Cancer. 2018 Oct 12;4:34. doi: 10.1038/s41523-018-0089-z. eCollection 2018.

Molecular determinants of post-mastectomy breast cancer recurrence.

Author information

1
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35249 UK.
2
2Department of Surgery, Dana Farber Cancer Institute, Boston, MA 02215 USA.
3
3Department of Surgery, Duke University, Durham, NC 27710 USA.
4
4Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
5
5Department of Surgery, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298 USA.
6
6Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
7
7Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065 USA.
8
Department of Statistics, University of Alabama at Birmingham, Birmingham, AL 35249 UK.
9
9Department of Surgery, Medical University of South Carolina, Charleston, SC 29425 USA.
10
10Department of Surgery, Vanderbilt University, Nashville, TN 37204 USA.
11
11Department of Surgery, University of Michigan Ann Arbor, Ann Arbor, MI 48109 USA.
12
Department of Surgery, Georgetown, Washington, DC 20007 USA.
13
13Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
14
14Department of Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065 USA.
15
15Department of Hematology and Oncology, John Hopkins University, Baltimore, MD 21287 USA.
16
16Department of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
#
Contributed equally

Abstract

Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1-3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1-3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM, or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM, and 25 controls) identified significantly more NF1 mutations and mitogen-activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p < 0.0001 and p = 0.0070, respectively). Three patients had matched primary vs. LRR samples, one patient had a gain of a NF1 mutation in the LRR. There was no significant difference between the groups for PTEN loss or cleaved caspase 3 expression. The mean percentage Ki 67 labeling index was higher in patients with LRR (29.2%) and DM (26%) vs. controls (14%, p = 0.0045). In summary, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in MAPK signaling are associated with a more aggressive tumor phenotype. Validation of these associations in tissues from randomized trials may support targeted therapy to reduce breast cancer recurrence.

Conflict of interest statement

Gordon B. Mills serves as a Consultant and/or on the Scientific Advisory Board for the following companies Allostery, Inc., AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMet, Ionis, Medimmune, Nuevolution, Precision Medicine, Signalchem Lifesciences, Symphogen, Takeda/Millenium Pharmaceuticals, Tarveda. He has a financial interest in Catena Pharmaceuticals, ImmunoMet, PTV Ventures, Spindletop Ventures. He holds licensed technology in HRD assay to Myriad Genetics. He has sponsored research from AstraZeneca, Critical Outcome Technologies, Illumina, Ionis, Karus, Nanostring, Takeda/Millenium Pharmaceuticals. Funda Meric Bernstam has grant or research support from Novartis, AstraZeneca, Taiho, Genentech, Calithera, Debiopharma, Bayer, PUMA, Aileron, Jounce, CytoMx, eFFECTOR, Zymeworks, Curis, Pfizer. She is a paid consultant for Dialecta, Sumitomo Dainippon Pharma. She is on advisory committees/review panels/board membership for Inflection Biosciences, Clearlight Diagnostics, Pieris, Darwin Health, GRAIL. Hong Zhang is a consultant for Genentech/Roche. Nancy Klauber-Demore is the Chief Scientific Officer, Co-founder and shareholder for Enci Therapeutic INC. The remaining authors declare no competing interests.

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