Biomarker Changes During Neoadjuvant Anastrozole, Tamoxifen, or the Combination: Influence of Hormonal Status and HER-2 in Breast Cancer—A Study from the IMPACT Trialists

Dowsett, Mitch; Ebbs, Steve R.; Dixon, J. Michael; Skene, Anthony; Griffith, Clive; Boeddinghaus, Irene; Salter, Janine; Detre, Simone; Hills, Margaret; Ashley, S.; Francis, Stephen; Walsh, Geraldine; Smith, Ian

doi:10.1200/jco.2005.07.559

Cited by 261 publications

(206 citation statements)

References 14 publications

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“…Consequently, measurements of Ki67 in individual cases do not accurately predict for subsequent pathological (or clinical) response. A similar lack of prediction between Ki67 changes and clinical response to anastrozole has been observed in the recently reported IMPACT neoadjuvant trial (Dowsett et al, 2005a) (although the short-term changes in proliferation did parallel recurrence-free survival between the three treatment groups, anastrozole, tamoxifen and Arimidex combined with tamoxifen) (Dowsett et al, 2005b). As a consequence, consideration therefore needs to be given as to why clear decreases in cellular proliferation at 10 -14 days do not translate into pathological response and why conversely responding cases can show no change or even an increase in Ki67 with treatment.…”

Section: Discussionsupporting

confidence: 63%

Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole

et al. 2006

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Sixty-three postmenopausal women with large primary breast cancers were treated with neoadjuvant letrozole (2.5 mg daily) for 3 months. Tumour samples were taken at diagnosis and after 10–14 days and 3 months treatment. Immunohistochemical staining for Ki67, oestrogen receptor (ER) and progesterone receptor (PgR) was performed and related to clinical (ClinR) and pathological responses (PathR) after 3 months treatment. ClinR was observed in 48 of 63 cases (76.2%) and PathR in 47 of 62 (75.8%). Pretreatment Ki67 scores were similar in responders (R) and non-responders (NR). Highly significant Ki67 decreases occurred in all tumour subgroups at 10–14 days ( P <0.005). A significant difference in Ki67 scores at 10–14 days ( P <0.007) was found between PathR and PathNR but not between ClinR and ClinNR. At 3 months, decreases from pretreatment Ki67 scores were highly significant in all tumour subgroups irrespective of response status. However, whereas Ki67 scores were significantly different between pathological R and NR ( P =0.009), the corresponding comparison of ClinR status was not. Significant decreases between 10–14 days and 3 months were found only in ClinR and PathR ( P =0.02 and 0.045, respectively). Treatment significantly reduced PgR expression at 14 days and 3 months (both P <0.0001), but the level of changes was not different between response status groups. In summary, letrozole produces rapid and profound decreases in expression of Ki67 and PgR but changes do not always correlate with clinical and pathological responses.

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Section: Discussionsupporting

confidence: 63%

Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole

et al. 2006

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“…PR LI was also significantly (PZ0.046) decreased after the exemestane therapy (39 (0-76) % before the therapy and 20 (0-67) % after the therapy), as previously reported in the anastrozole treatment (Dowsett et al 2005a). On the other hand, ER LI, AR LI, and HER2 status were not significantly different in each case between before and after the exemestane therapy in this study (PZ0.42, PZ0.16, and PZ0.56 respectively).…”

Section: Immunolocalization Of Sex Steroid-related Enzymes In Breast supporting

confidence: 66%

Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment

Takagi

Miki

Nagasaki³

et al. 2010

Endocrine-Related Cancer

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Sex steroids play important roles in the development of many human breast carcinomas, and aromatase inhibitors are used for the anti-estrogen therapy. Recent studies have demonstrated that aromatase suppressed 5a-dihydrotestosterone (DHT) synthesis in breast carcinoma cells, but intratumoral concentration of androgens and its significance have not been reported in the breast carcinoma patients treated with aromatase inhibitors. Therefore, we examined androgen concentrations in breast carcinoma tissues treated with exemestane, and further performed in vitro studies to characterize the significance of androgen actions. Intratumoral DHT concentration was significantly higher in breast carcinoma tissues following exemestane treatment (nZ9) than those without the therapy (nZ7), and 17b-hydroxysteroid dehydrogenase type 2 (17bHSD2) status was significantly altered to be positive after the treatment. Following in vitro studies showed that 17bHSD2 expression was dose dependently induced by both DHT and exemestane in T-47D breast carcinoma cells, but these inductions were not additive. DHT-mediated induction of 17bHSD2 expression was markedly suppressed by estradiol (E 2 ) in T-47D cells. E 2 -mediated cell proliferation was significantly inhibited by DHT in T-47D cells, associated with an increment of 17bHSD2 expression level. These findings suggest that intratumoral androgen actions are increased during exemestane treatment. 17bHSD2 is a potent DHT-induced gene in human breast carcinoma, and may not only be involved in anti-proliferative effects of DHT on breast carcinoma cells but also serve as a potential marker for response to aromatase inhibitor in the breast carcinoma patients.

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“…The target study size was 40 patients but difficulties with competing studies led to its termination after 25 patients. This curtailment of the study inevitably led to loss of statistical power but the data analyzed allowed instructive comparisons with earlier presurgical studies of aromatase inhibitors to be made [40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Pre-surgical study of the biological effects of the selective cyclo-oxygenase-2 inhibitor celecoxib in patients with primary breast cancer

Martin

Davies

Weigel

et al. 2010

Breast Cancer Res Treat

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Biomarker Changes During Neoadjuvant Anastrozole, Tamoxifen, or the Combination: Influence of Hormonal Status and HER-2 in Breast Cancer—A Study from the IMPACT Trialists

Cited by 261 publications

References 14 publications

Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole

Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole

Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment

Pre-surgical study of the biological effects of the selective cyclo-oxygenase-2 inhibitor celecoxib in patients with primary breast cancer

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