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Akt kinases in breast cancer and the results of adjuvant therapy.

Stål O, Pérez-Tenorio G, Akerberg L, Olsson B, Nordenskjöld B, Skoog L, Rutqvist LE - Breast Cancer Res. (2003)

Bottom Line: The benefit from tamoxifen was analysed in oestrogen receptor (ER)-positive patients.Patients with a negative status of Akt (no overexpression of Akt1, Akt2 or pAkt) showed significant benefit from tamoxifen.The difference in rate ratio did not reach statistical significance.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biomedicine and Surgery, Division of Oncology, Faculty of Health Sciences, Linköping University, Linköping, Sweden. olle.stal@onk.liu.se

ABSTRACT

Background: The serine/threonine kinase Akt, or protein kinase B, has recently been a focus of interest because of its activity to inhibit apoptosis. It mediates cell survival by acting as a transducer of signals from growth factor receptors that activate phosphatidylinositol 3-kinase.

Methods: We analysed the expression of the isoforms Akt1 and Akt2 as well as phosphorylated Akt (pAkt) by immunohistochemistry in frozen tumour samples from 280 postmenopausal patients who participated in a randomised trial comparing cyclophosphamide-methotrexate-5-fluorouracil chemotherapy and postoperative radiotherapy. The patients were simultaneously randomised to tamoxifen or to no endocrine treatment.

Results: Marked staining was found in 24% of the tumours for Akt1, but in only 4% for Akt2. A low frequency of Akt2-positive cells (1-10%) was observed in another 26% of the tumours. pAkt was significantly associated with both Akt1 and Akt2 expression. Overexpression of erbB2 correlated significantly with pAkt (P = 0.0028). The benefit from tamoxifen was analysed in oestrogen receptor (ER)-positive patients. Patients with a negative status of Akt (no overexpression of Akt1, Akt2 or pAkt) showed significant benefit from tamoxifen. The relative rate of distant recurrence, with versus without tamoxifen, was 0.44 (95% confidence interval [CI], 0.25-0.79) for ER+/Akt1- patients, while it was 0.72 (95% CI, 0.34-1.53) for ER+/Akt1+ patients. The difference in rate ratio did not reach statistical significance. The rate of locoregional recurrence was significantly decreased with radiotherapy versus chemotherapy for Akt-negative patients (rate ratio, 0.23; 95% CI, 0.08-0.67; P = 0.0074), while no benefit was evident for the Akt-positive subgroup (rate ratio, 0.77; 95% CI, 0.31-1.9; P = 0.58). The interaction between Akt and the efficacy of radiotherapy was significant in multivariate analysis (P = 0.042).

Conclusion: Activation of the Akt pathway is correlated with erbB2 overexpression in breast cancer. The results suggest that Akt may predict the local control benefit from radiotherapy.

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Related in: MedlinePlus

Distant recurrence-free survival for oestrogen receptor (ER)-positive patients treated with tamoxifen (TAM) or not (no TAM) in relation to Akt status.
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Figure 2: Distant recurrence-free survival for oestrogen receptor (ER)-positive patients treated with tamoxifen (TAM) or not (no TAM) in relation to Akt status.

Mentions: We next investigated a possible interaction between the expression of Akt and the benefit from tamoxifen for ER-positive patients. To increase the statistical power, patients whose tumours showed strong staining (> 10%) for either Akt1, Akt2 or pAkt were grouped together and were defined as Akt-positive. The benefit from tamoxifen was largely confined to ER+/Akt- patients (Fig. 2). In this group, adjuvant tamoxifen decreased the risk of distant recurrence by 56% (rate ratio [RR] = 0.44; 95% CI, 0.25–0.79), while the risk reduction was not statistically significant for Akt-negative patients (RR = 0.72; 95% CI, 0.34–1.53). The interaction between Akt and tamoxifen did not reach statistical significance in multivariate analysis that also included other tumour characteristics (P = 0.28; Table 4). Likewise, the erbB2 status failed to predict the benefit from tamoxifen; however, the ER+/erbB2+ subgroup comprised only 39 patients (data not shown).


Akt kinases in breast cancer and the results of adjuvant therapy.

Stål O, Pérez-Tenorio G, Akerberg L, Olsson B, Nordenskjöld B, Skoog L, Rutqvist LE - Breast Cancer Res. (2003)

Distant recurrence-free survival for oestrogen receptor (ER)-positive patients treated with tamoxifen (TAM) or not (no TAM) in relation to Akt status.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC154147&req=5

Figure 2: Distant recurrence-free survival for oestrogen receptor (ER)-positive patients treated with tamoxifen (TAM) or not (no TAM) in relation to Akt status.
Mentions: We next investigated a possible interaction between the expression of Akt and the benefit from tamoxifen for ER-positive patients. To increase the statistical power, patients whose tumours showed strong staining (> 10%) for either Akt1, Akt2 or pAkt were grouped together and were defined as Akt-positive. The benefit from tamoxifen was largely confined to ER+/Akt- patients (Fig. 2). In this group, adjuvant tamoxifen decreased the risk of distant recurrence by 56% (rate ratio [RR] = 0.44; 95% CI, 0.25–0.79), while the risk reduction was not statistically significant for Akt-negative patients (RR = 0.72; 95% CI, 0.34–1.53). The interaction between Akt and tamoxifen did not reach statistical significance in multivariate analysis that also included other tumour characteristics (P = 0.28; Table 4). Likewise, the erbB2 status failed to predict the benefit from tamoxifen; however, the ER+/erbB2+ subgroup comprised only 39 patients (data not shown).

Bottom Line: The benefit from tamoxifen was analysed in oestrogen receptor (ER)-positive patients.Patients with a negative status of Akt (no overexpression of Akt1, Akt2 or pAkt) showed significant benefit from tamoxifen.The difference in rate ratio did not reach statistical significance.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biomedicine and Surgery, Division of Oncology, Faculty of Health Sciences, Linköping University, Linköping, Sweden. olle.stal@onk.liu.se

ABSTRACT

Background: The serine/threonine kinase Akt, or protein kinase B, has recently been a focus of interest because of its activity to inhibit apoptosis. It mediates cell survival by acting as a transducer of signals from growth factor receptors that activate phosphatidylinositol 3-kinase.

Methods: We analysed the expression of the isoforms Akt1 and Akt2 as well as phosphorylated Akt (pAkt) by immunohistochemistry in frozen tumour samples from 280 postmenopausal patients who participated in a randomised trial comparing cyclophosphamide-methotrexate-5-fluorouracil chemotherapy and postoperative radiotherapy. The patients were simultaneously randomised to tamoxifen or to no endocrine treatment.

Results: Marked staining was found in 24% of the tumours for Akt1, but in only 4% for Akt2. A low frequency of Akt2-positive cells (1-10%) was observed in another 26% of the tumours. pAkt was significantly associated with both Akt1 and Akt2 expression. Overexpression of erbB2 correlated significantly with pAkt (P = 0.0028). The benefit from tamoxifen was analysed in oestrogen receptor (ER)-positive patients. Patients with a negative status of Akt (no overexpression of Akt1, Akt2 or pAkt) showed significant benefit from tamoxifen. The relative rate of distant recurrence, with versus without tamoxifen, was 0.44 (95% confidence interval [CI], 0.25-0.79) for ER+/Akt1- patients, while it was 0.72 (95% CI, 0.34-1.53) for ER+/Akt1+ patients. The difference in rate ratio did not reach statistical significance. The rate of locoregional recurrence was significantly decreased with radiotherapy versus chemotherapy for Akt-negative patients (rate ratio, 0.23; 95% CI, 0.08-0.67; P = 0.0074), while no benefit was evident for the Akt-positive subgroup (rate ratio, 0.77; 95% CI, 0.31-1.9; P = 0.58). The interaction between Akt and the efficacy of radiotherapy was significant in multivariate analysis (P = 0.042).

Conclusion: Activation of the Akt pathway is correlated with erbB2 overexpression in breast cancer. The results suggest that Akt may predict the local control benefit from radiotherapy.

Show MeSH
Related in: MedlinePlus