Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Long-term prognostic and predictive factors in hormone receptor positive breast cancer
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
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: urn:nbn:se:liu:diva-145398DOI: 10.3384/diss.diva-145398ISBN: 9789176853726 (print)OAI: oai:DiVA.org:liu-145398DiVA, id: diva2:1186353
Public defence
2018-03-29, Hasselquistsalen, Hus 511, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-02-28Bibliographically approved
List of papers
1. Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer
Open this publication in new window or tab >>Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer
Show others...
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
Keywords
Breast cancer, Akt, Protein kinase B, Oestrogen receptor, Long-term, Prognostic factor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-92610 (URN)10.1016/j.ejca.2012.12.006 (DOI)000317188600005 ()
Note

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

Available from: 2013-05-16 Created: 2013-05-14 Last updated: 2018-02-28
2. Progesterone receptor positivity is a predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer
Open this publication in new window or tab >>Progesterone receptor positivity is a predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer
Show others...
2016 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 160, no 2, p. 313-322Article in journal (Refereed) Published
Abstract [en]

The independent predictive information from progesterone receptor (PgR) positivity for breast cancer treated with tamoxifen has been questioned after an overview by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). However, the studies in the overview were to a large content performed before modern PgR immunohistochemistry (IHC) was developed. We therefore investigated the predictive value of PgR determined with IHC in estrogen receptor (ER)-positive tumors from patients participating in the Stockholm trial of adjuvant tamoxifen therapy. The Stockholm Breast Cancer Study Group conducted a randomized trial during 1976 through 1990 comparing adjuvant tamoxifen versus control. The patients were stratified according to tumor size and lymph node status in high-risk and low-risk groups. In this study, we evaluated 618 patients with ER-positive "low-risk" breast cancer (size aecurrency sign 30 mm, lymph node-negative) for whom PgR was determined by IHC at one pathology laboratory. The median time of follow-up was 21 years. Patients with ER-positive tumors that were also PgR-positive by IHC did benefit from tamoxifen, while we could not show any long-term benefit for those with tumors positive for ER only (recurrence rate ratio 0.43, 95 % CI 0.29-0.62 and 0.87, 95 % CI 0.52-1.46, respectively). We further investigated the influence of different levels of PgR positivity on recurrence risk. The results show that at all receptor levels with aeyen10 % stained PgR-positive cells, the patients did benefit from tamoxifen. There was no clear linear trend in benefit with increasing proportion of stained cells. PgR positivity determined by IHC is a marker indicating long-term benefit from adjuvant tamoxifen in patients with ER-positive tumors.

Place, publisher, year, edition, pages
SPRINGER, 2016
Keywords
Breast cancer; Tamoxifen; Estrogen receptor; Progesterone receptor
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-132653 (URN)10.1007/s10549-016-4007-5 (DOI)000386370400012 ()27722840 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Swedish Breast Cancer Association; Cancer Research Foundations of Radiumhemmet; Cancer Society in Stockholm; King Gustav V Jubilee Clinical Research Foundation; County Council of Ostergotland; Onkologiska Klinikernas i Linkoping Forskningsfond

Available from: 2016-11-21 Created: 2016-11-18 Last updated: 2018-02-28

Open Access in DiVA

Long-term prognostic and predictive factors in hormone receptor positive breast cancer(1177 kB)57 downloads
File information
File name FULLTEXT01.pdfFile size 1177 kBChecksum SHA-512
63e590a20425e30c45925dd17e368c7a601198fb603c7e75b4cd77d55b2cc754bf9bf51f4aa2bbd8b169f0f96174b2e8c13c90ccd20bf47e74a30276ca42e16c
Type fulltextMimetype application/pdf
omslag(70 kB)6 downloads
File information
File name COVER01.pdfFile size 70 kBChecksum SHA-512
32ed393c340abf6901789ee327499f93ec604ed220e9dd358692f364ed44f8df717cef0d9bbab341ddf53dd304cf056cb2d7018b01d1ad04fcae3c1b9b76eeb1
Type coverMimetype application/pdf

Other links

Publisher's full text

Search in DiVA

By author/editor
Fohlin, Helena
By organisation
Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health Sciences
Cancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar
Total: 57 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
isbn
urn-nbn

Altmetric score

doi
isbn
urn-nbn
Total: 427 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf