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Progesterone receptor positivity is a predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer
Sahlgrens Acad, Sweden; Southern Alvsborg Hospital, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
Karolinska University Hospital, Sweden; Karolinska Institute, Sweden; Regional Cancer Centre Stockholm Gotland, Sweden.
St Göran Hospital, Sweden.
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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. Vol. 160, no 2, p. 313-322
Keywords [en]
Breast cancer; Tamoxifen; Estrogen receptor; Progesterone receptor
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-132653DOI: 10.1007/s10549-016-4007-5ISI: 000386370400012PubMedID: 27722840OAI: oai:DiVA.org:liu-132653DiVA, id: diva2:1048385
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
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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