Pak1, adjuvant tamoxifen therapy, and breast cancer recurrence risk in a Danish population-based study

• Type of Material: Article
• Authors: Thomas P. Ahern, University of Vermont College of Medicine; Deirdre P. Cronin-Fenton, Aarhus University Hospital; Timothy Lash, Emory University; Henrik Toft Sorensen, Aarhus University Hospital; Anne Gulbech Ording, Aarhus University Hospital; Stephen J. Hamilton-Dutoit, Aarhus University Hospital; Ylva Hellberg, Aarhus University Hospital
• Language: English
• Date: 2016-04-08
• Publisher: Taylor & Francis
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Informa UK Limited, trading as Taylor & Francis Group. This is an Accepted Manuscript of an article published by Taylor & Francis in Acta Oncologica on 08 Apr 2016, available online: http://www.tandfonline.com/doi:10.3109/0284186X.2016.1150606.
• Final Published Version (URL): http://dx.doi.org/10.3109/0284186X.2016.1150606
• Title of Journal or Parent Work: Acta Oncologica
• ISSN: 0284-186X
• Volume: 55
• Issue: 6
• Start Page: 734
• End Page: 741
• Grant/Funding Information: This study was supported by the Danish Medical Research Council [DOK 1158859 (T. L. Lash)] US National Cancer Institute at the US National Institutes of Health [R01 CA118708 and R01 CA166825 (T. L. Lash) and T32 CA09001-35 (T. P. Ahern)]; Danish Cancer Society [DP06117 (S. Hamilton-Dutoit)]; Karen Elise Jensen Foundation (H. T. Sørensen); Congressionally Directed Medical Research Programs [BC073012 (T. P. Ahern)]; and Susan G. Komen for the Cure [CCR13264024 (T. P. Ahern)]; and the Lundbeck Foundation [R167-2013-15861 (D. P. Cronin-Fenton)].
• Keywords: TERM-FOLLOW-UP; ESTROGEN-RECEPTOR-ALPHA; COOPERATIVE-GROUP DBCG; P21-ACTIVATED-KINASE-1; Science & Technology; Oncology; RESISTANCE; SUFFICIENT; PHOSPHORYLATION; Life Sciences & Biomedicine; SERINE 305; EXPRESSION; VALIDATION
• Research Categories: Health Sciences, Pathology; Health Sciences, Epidemiology; Health Sciences, Public Health

Abstract

Background: Adjuvant tamoxifen therapy approximately halves the risk of estrogen receptor-positive (ER+) breast cancer recurrence, but many women do not respond to therapy. Observational studies nested in clinical trial populations suggest that overexpression or nuclear localization of p21-activated kinase 1 (Pak1) in primary tumors predicts tamoxifen failure. Material and methods: We measured the association between Pak1 expression and breast cancer recurrence in a Danish population-based case-control study. Pak1 cytoplasmic expression level and nuclear positivity were determined by immunohistochemical staining of primary breast tumors from recurrence cases and matched controls from two breast cancer populations; women diagnosed with ER-positive tumors who received at least one year of tamoxifen therapy (ER+/TAM+), and women diagnosed with ER-negative tumors who survived for at least one year (ER−/TAM−). Pak1 staining was assessed by a single, blinded pathologist, and associations were estimated with conditional logistic regression models. Results: We included 541 recurrence cases and 1:1 matched controls from the ER+/TAM + group and 300 recurrence cases and 1:1 matched controls from the ER−/TAM − group. Pak1 cytoplasmic intensity was not associated with breast cancer recurrence in either group (ER+/TAM + ORadj for strong vs. no cytoplasmic staining = 0.91, 95% CI 0.57, 1.5; ER−/TAM − ORadj for strong vs. no cytoplasmic staining = 0.74, 95% CI 0.39, 1.4). Associations between Pak1 nuclear positivity and breast cancer recurrence were similarly near null in both groups. Conclusion: Pak1 positivity in primary breast tumors was neither predictive nor prognostic in this prospective, population-based study.