Molecular determinants of post-mastectomy breast cancer recurrence

Kimberly S. Keene, Tari King, E. Shelley Hwang, Bo Peng, Kandace P. McGuire, Coya Tapia, Hong Zhang, Sejong Bae, Faina Nakhlis, Nancy Klauber-Demore, Ingrid Meszoely, Michael S. Sabel, Shawna C. Willey, Agda Karina Eterovic, Cliff Hudis, Antonio C. Wolff, Jennifer De Los Santos, Alastair Thompson, Gordon Mills, Funda Meric-Bernstam

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number34
Journalnpj Breast Cancer
Volume4
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

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Mastectomy
Breast Neoplasms
Recurrence
Neoplasm Metastasis
Mitogen-Activated Protein Kinases
Mutation
Neoplasms
Caspase 3
Radiotherapy
Therapeutics
Lymph Nodes
RNA
Phenotype
DNA

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology (medical)

Cite this

Keene, K. S., King, T., Hwang, E. S., Peng, B., McGuire, K. P., Tapia, C., ... Meric-Bernstam, F. (2018). Molecular determinants of post-mastectomy breast cancer recurrence. npj Breast Cancer, 4(1), [34]. https://doi.org/10.1038/s41523-018-0089-z

Molecular determinants of post-mastectomy breast cancer recurrence. / Keene, Kimberly S.; King, Tari; Hwang, E. Shelley; Peng, Bo; McGuire, Kandace P.; Tapia, Coya; Zhang, Hong; Bae, Sejong; Nakhlis, Faina; Klauber-Demore, Nancy; Meszoely, Ingrid; Sabel, Michael S.; Willey, Shawna C.; Eterovic, Agda Karina; Hudis, Cliff; Wolff, Antonio C.; De Los Santos, Jennifer; Thompson, Alastair; Mills, Gordon; Meric-Bernstam, Funda.

In: npj Breast Cancer, Vol. 4, No. 1, 34, 01.12.2018.

Research output: Contribution to journalArticle

Keene, KS, King, T, Hwang, ES, Peng, B, McGuire, KP, Tapia, C, Zhang, H, Bae, S, Nakhlis, F, Klauber-Demore, N, Meszoely, I, Sabel, MS, Willey, SC, Eterovic, AK, Hudis, C, Wolff, AC, De Los Santos, J, Thompson, A, Mills, G & Meric-Bernstam, F 2018, 'Molecular determinants of post-mastectomy breast cancer recurrence', npj Breast Cancer, vol. 4, no. 1, 34. https://doi.org/10.1038/s41523-018-0089-z
Keene KS, King T, Hwang ES, Peng B, McGuire KP, Tapia C et al. Molecular determinants of post-mastectomy breast cancer recurrence. npj Breast Cancer. 2018 Dec 1;4(1). 34. https://doi.org/10.1038/s41523-018-0089-z
Keene, Kimberly S. ; King, Tari ; Hwang, E. Shelley ; Peng, Bo ; McGuire, Kandace P. ; Tapia, Coya ; Zhang, Hong ; Bae, Sejong ; Nakhlis, Faina ; Klauber-Demore, Nancy ; Meszoely, Ingrid ; Sabel, Michael S. ; Willey, Shawna C. ; Eterovic, Agda Karina ; Hudis, Cliff ; Wolff, Antonio C. ; De Los Santos, Jennifer ; Thompson, Alastair ; Mills, Gordon ; Meric-Bernstam, Funda. / Molecular determinants of post-mastectomy breast cancer recurrence. In: npj Breast Cancer. 2018 ; Vol. 4, No. 1.
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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 na{\"i}ve, 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.",
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AU - Keene, Kimberly S.

AU - King, Tari

AU - Hwang, E. Shelley

AU - Peng, Bo

AU - McGuire, Kandace P.

AU - Tapia, Coya

AU - Zhang, Hong

AU - Bae, Sejong

AU - Nakhlis, Faina

AU - Klauber-Demore, Nancy

AU - Meszoely, Ingrid

AU - Sabel, Michael S.

AU - Willey, Shawna C.

AU - Eterovic, Agda Karina

AU - Hudis, Cliff

AU - Wolff, Antonio C.

AU - De Los Santos, Jennifer

AU - Thompson, Alastair

AU - Mills, Gordon

AU - Meric-Bernstam, Funda

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