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Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Karolinska University Hospital, Sweden.
Karolinska University Hospital, Sweden.
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2013 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no 6, p. 1196-1204Article in journal (Refereed) Published
Abstract [en]

Introduction

Akt is a signalling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of v-akt murine thymoma viral oncogene homologue 1 (Akt1) and v-akt murine thymoma viral oncogene homologue 2 (Akt2) in oestrogen receptor positive (ER+) and oestrogen receptor negative (ER–) breast cancer with long-term follow-up.

Material and methods

The expression of Akt in tumour tissue was analysed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. The median follow-up time was 19 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox’s proportional hazards model.

Results

The risk of distant recurrence was reduced for patients with ER+ tumours expressing Akt2 compared to patients with no Akt2 expression (HR = 0.49, 95% CI 0.29–0.82, p = 0.007). When adjusting for important clinical tumour characteristics and treatment, Akt2 was still an independent prognostic factor (HR = 0.38, 95% CI 0.21–0.68, p = 0.001) and the association remained long-term. The prognostic value of Akt2 increased with higher oestrogen receptor levels from no effect among patients with ER– tumours to 68% risk reduction for the group with high ER-levels (P for trend = 0.042). Akt1 showed no significant prognostic information.

Conclusion

Our results indicate that Akt2 expression is associated with a lower distant recurrence rate for patients with ER+ tumours and that this association remains long-term. The prognostic value of Akt2 increases with higher oestrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer.

Place, publisher, year, edition, pages
Elsevier , 2013. Vol. 49, no 6, p. 1196-1204
Keyword [en]
Breast cancer, Akt, Protein kinase B, Oestrogen receptor, Long-term, Prognostic factor
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-92610DOI: 10.1016/j.ejca.2012.12.006ISI: 000317188600005OAI: oai:DiVA.org:liu-92610DiVA, id: diva2:621697
Note

Funding Agencies|Swedish Cancer Society||Swedish Research Council||

Available from: 2013-05-16 Created: 2013-05-14 Last updated: 2018-02-28
In thesis
1. Long-term prognostic and predictive factors in hormone receptor positive breast cancer
Open this publication in new window or tab >>Long-term prognostic and predictive factors in hormone receptor positive breast cancer
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The breast cancer survival in Sweden is good (almost 90 % 5-year relative survival) and has increased over time. For women with hormone receptor negative tumors, most relapses occur within the first 5 years after diagnosis. Thereafter the recurrence risk decreases rapidly. For women with estrogen receptor positive (ER+) tumors the annual risk for late recurrences is 1 – 2 %, even after 5 years of endocrine therapy. This risk accumulates so that approximately 25 % of the patients that are recurrence-free after five years from diagnosis may experience a relapse within further 15 years of follow-up. The relatively high long-term risk calls for identification of prognostic and predictive markers with long-term effect. Though, the number of such markers with proven significance is limited. Of the clinical characteristics, only nodal status and to some extent tumor size and tumor grade have been shown to have long-term prognostic value. In this thesis, we propose long-term prognostic and predictive markers for breast cancer.

In paper I, we suggest the protein v-akt murine thymoma viral oncogene homologue 2 (AKT2) as a long-term prognostic marker among patients with ER+ tumors. In our study, besides nodal status, AKT2 was the only factor with long-term prognostic value. This is in accordance with some other studies, though we also showed that the significance of AKT2 was limited to ER+ tumors and that the impact increased with higher ER expression.

Approximately 75 – 85 % of the ER+ tumors are also progesterone receptor positive (PR+). ER+/progesterone receptor negative (PR-) tumors are considered to be more aggressive and patients with such tumors are often treated with chemotherapy. In this group, more specific subgroups for targeted therapy are needed.

Whereas ER has long been established as a predictive factor regarding tamoxifen benefit, the role of PR has not been clarified to date. In paper II, we showed that PR status adds predictive value to ER considering the long-term benefit from tamoxifen.

In paper III, we aimed to identify new prognostic markers among patients with ER+ tumors. Systemically untreated patients with ER+/PR- tumors and high expression of the Ras-related protein RAB6C (RAB6C) had reduced distant recurrence rate. Therefore, we suggest RAB6C as a candidate marker for subgroup division among patients with ER+/PR- tumors.

According to the results from paper II, there might be subgroups of patients with ER+/PRtumors that do benefit from tamoxifen. The aim of paper IV was to identify such subgroups. Here, we suggest that patients with ER+/PR- tumors and low RAB6C expression do benefit from tamoxifen.

The results from this thesis may encourage further studies for more specific subgroup divisions. Such studies may lead to changes in the management program, where some patients with ER+ tumors should receive prolonged or more intense treatment and others reduced treatment based on the pathological markers AKT2, PR and RAB6C. 

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 64
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1607
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-145398 (URN)10.3384/diss.diva-145398 (DOI)9789176853726 (ISBN)
Public defence
2018-03-29, Hasselquistsalen, Hus 511, Campus US, Linköping, 09:00 (English)
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Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-02-28Bibliographically approved

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Fohlin, HelenaPerez-Tenorio, GizehNordenskjöld, BoCarstensen, JohnStål, Olle

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