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- Bostner, Josefine, et al.
(författare)
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Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer.
- 2007
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 26:49, s. 6997-7005
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Tidskriftsartikel (refereegranskat)abstract
- The 11q13 region is amplified in approximately 15% of all breast tumors. Situated in this region are the cyclin D1 gene (CCND1) and the p-21-activated kinase 1 (PAK1) gene. Both genes encode proteins shown to activate the estrogen receptor (ER), leading to transcription of CCND1 and other ER-responsive genes. Here, we investigate the prognostic and treatment predictive role of CCND1 and PAK1 gene amplification in postmenopausal breast cancer patients randomized to tamoxifen treatment or no adjuvant treatment. Amplification of CCND1 and PAK1, assessed by real-time PCR, was observed in 12.5 and 9.3%, respectively. Amplification of PAK1 was seen in 37% of the CCND1-amplified tumors, indicating coamplification (P<0.001). In ER-positive patients, amplification of at least one of the genes indicated a reduced recurrence-free survival (P=0.025). When response to tamoxifen treatment was analysed, patients with PAK1 amplification showed decreased benefit from the drug (ER+; relative risk ratio (RR)=1.62; 95% confidence interval (CI), 0.47-5.55) compared to patients without amplification (ER+; RR=0.53; 95% CI, 0.32-0.88). This was not evident for CCND1 amplification. We show that PAK1 may be a predictor of tamoxifen resistance and furthermore, we do not discard PAK1 as a potential candidate oncogene in the 11q13 amplicon. In addition, we show that high pak1 protein levels may predict tamoxifen insensitivity.
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| 2. |
- Jerevall, Piiha-Lotta, et al.
(författare)
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HOXB13 protein expression predicts the benefit of tamoxifen treatment in breast cancer patients : in CANCER RESEARCH, vol 69, issue 2, Supplement 1, pp 358S-358S
- 2009
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Ingår i: CANCER RESEARCH. ; , s. 358S-358S
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Konferensbidrag (refereegranskat)abstract
- Background: The two-gene expression ratio HOXB13:IL17BR, originally from a microarray analysis, has been shown to be indicative of clinical outcome in the setting of adjuvant tamoxifen monotherapy of breast cancer, with a high ratio associated with decreased disease-free survival. Analysis of a cohort of breast cancer patients randomized to 2 or 5 years of adjuvant tamoxifen therapy showed that the two-gene ratio and expression of the HOXB13 gene alone were predictive of the benefit of prolonged tamoxifen treatment. Patients with tumors expressing HOXB13 at high levels were unresponsive to prolonged adjuvant treatment, suggesting that this gene is involved in tamoxifen resistance. It is suggested that a high two-gene ratio may indicate impaired ER signaling, which is known to predict resistance to tamoxifen. To our knowledge, there are no studies investigating the HOXB13 protein levels in breast cancer. Methods: We have analyzed the protein expression of HOXB13 with immunohistochemistry in tumor samples from 912 postmenopausal node negative breast cancer patients randomized to 2 years of tamoxifen or no endocrine treatment. After 2 years, recurrence-free patients were randomized to 3 more years of tamoxifen, or no further therapy. This selection enabled us to investigate the treatment predictive value of HOXB13. Results: Data on HOXB13 protein expression were obtained from 866 patients (see table). Tamoxifen treated patients with estrogen receptor (ER) positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (hazard ratio (HR) 0.37, 95% CI 0.23-0.60, p=0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the distant recurrence-free survival compared to the untreated patients (HR=0.83, 95% CI 0.45-1.54, p=0.55). The interaction between HOXB13 expression and benefit from tamoxifen was statistically significant (p=0.046). HOXB13 did not have any prognostic value among systemically untreated patients.
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| 3. |
- Nordenskjöld, Anna, 1969, et al.
(författare)
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Progesterone receptor positivity is a predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer
- 2016
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 160:2, s. 313-322
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: 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. Methods: 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≤30mm, lymph node-negative) for whom PgR was determined by IHC at one pathology laboratory. The median time of follow-up was 21years. Results: 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≥10% stained PgR-positive cells, the patients did benefit from tamoxifen. There was no clear linear trend in benefit with increasing proportion of stained cells. Conclusions: PgR positivity determined by IHC is a marker indicating long-term benefit from adjuvant tamoxifen in patients with ER-positive tumors. © 2016, The Author(s).
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| 6. |
- Weiner, Maria, et al.
(författare)
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Oestrogen receptor co-activator AIB1 is a marker of tamoxifen benefit in postmenopausal breast cancer
- 2013
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Ingår i: Annals of Oncology. - : Oxford University Press. - 0923-7534 .- 1569-8041. ; 24:8, s. 1994-1999
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Tidskriftsartikel (refereegranskat)abstract
- Background The oestrogen receptor (ER) co-activator amplified in breast cancer 1 (AIB1) has been suggested as a treatment predictive and prognostic marker in breast cancer. Studies have however not been unanimous.Patients and methods AIB1 protein expression was analysed by immunohistochemistry on tissue micro-arrays with tumour samples from 910 postmenopausal women randomised to tamoxifen treatment or no adjuvant treatment. Associations between AIB1 expression, clinical outcome in the two arms and other clinicopathological variables were examined.Results In patients with ER-positive breast cancer expressing low tumour levels of AIB1 (<75%), we found no significant difference in recurrence-free survival (RFS) or breast cancer-specific survival (BCS) between tamoxifen treated and untreated patients. In patients with high AIB1 expression (>75%), there was a significant decrease in recurrence rate (HR 0.40, 95% CI 0.26–0.61, P < 0.001) and breast cancer mortality rate (HR 0.38, 95% CI 0.21–0.69, P = 0.0015) with tamoxifen treatment. In the untreated arm, we found high expression of AIB1 to be significantly associated with lower RFS (HR 1.74, 95% CI 1.20–2.53, P = 0.0038).Conclusion Our results suggest that high AIB1 is a predictive marker of good response to tamoxifen treatment in postmenopausal women and a prognostic marker of decreased RFS in systemically untreated patients.
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