Comparison of the Systemic and Intratumoral Effects of Tamoxifen and the Aromatase Inhibitor Vorozole in Postmenopausal Patients With Primary Breast Cancer

Harper‐Wynne, Catherine; Sacks, N. P. M.; Shenton, Karyn; MacNeill, Fiona; Sauven, P.; Laidlaw, Ian; Rayter, Z.; Miall, Stephanie; Howes, Angela; Salter, Janine; Hills, Margaret; Lowe, Frances M.; A’Hern, Roger; Nasiri, N.; Doody, Debbie; Iqbal, Jhangir; Dowsett, Mitchell

doi:10.1200/jco.2002.20.4.1026

Cited by 58 publications

(35 citation statements)

References 39 publications

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“…The same group have also presented results from a randomised neoadjuvant trial comparing the aromatase inhibitor vorozole with tamoxifen. Ki67 levels fell within 2 weeks of treatment and remained suppressed at surgery 3 months later (Harper-Wynne et al, 2002). These effects are therefore apparent before evidence of morphological changes in tumour pathology and clinical evidence of changes in tumour volume.…”

Section: Discussionmentioning

confidence: 84%

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: Discussionmentioning

confidence: 84%

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

et al. 2006

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“…In OR-positive IBC, changes in cellular proliferation measured by Ki67 nuclear antigen labelling can be used to reliably predict the response to antioestrogen therapy (Clarke et al, 1993;Chang et al, 2000;Dowsett et al, 2001a;Robertson et al, 2001;Harper-Wynne et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Studies of patients with IBC have shown that early changes (o3 weeks) in cell proliferative indices and PR expression occur after antioestrogen therapy (Clarke et al, 1993;Chang et al, 2000;Dowsett et al, 2001a;Robertson et al, 2001;Harper-Wynne et al, 2002) in OR-positive (but not OR-negative) tumours and these changes are accepted as surrogate markers of clinical tumour response, with tamoxifen treatment increasing (Chang et al, 2000;Robertson et al, 2001) and aromatase inhibitor therapy decreasing PR expression .…”

mentioning

confidence: 99%

Biological response to hormonal manipulation in oestrogen receptor positive ductal carcinoma in situ of the breast

Boland¹,

McKeown²,

Chan³

et al. 2003

Br J Cancer

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Adjuvant antioestrogen therapy with tamoxifen is recommended for all women following breast-conserving surgery for ductal carcinoma in situ (DCIS) to reduce local recurrence, despite 50% of lesions being oestrogen receptor (OR) negative. We have investigated the response to hormone manipulation in DCIS by studying changes in epithelial proliferation and progesterone receptor (PR) expression as surrogate molecular markers of treatment effects in DCIS of known OR status. Women were identified who had undergone diagnostic core biopsy followed by surgery for DCIS 14 -41 days later. Ki67 (a measure of epithelial cell proliferation) and PR expression were determined by immunohistochemistry on paired paraffin sections of the core biopsy and operative specimens for each patient, with OR and HER-2 measured on the operative specimen. Women were divided into three groups according to whether they had changed hormone therapy (stopped hormone replacement therapy (HRT), group 1), continued taking HRT (group 2) or were not taking HRT (group 3) between core biopsy and surgery. In OR-positive (but not in OR-negative) DCIS after oestrogen withdrawal (group 1), a fall in the mean cell proliferation (Po0.01) was observed. A fall in PR expression between core biopsy and surgery was also seen in this group (P ¼ 0.02). No change in either mean cell proliferation or PR expression was seen in the other two groups in OR-positive or -negative DCIS. The fall in proliferation and PR expression occurred regardless of HER-2 status. In conclusion, a biological response to hormone manipulation is only seen in OR-positive DCIS tumours. Any clinical value of antioestrogen therapy is likely to be restricted to this group.

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“…Data from relatively small studies supported the possibility that biomarkers may predict tumor response to chemotherapy (Chang et al 2000). In a neoadjuvant endocrine therapy trial, the aromatase inhibitor vorozole was compared with tamoxifen, and after 2 weeks it showed a greater fall in Ki-67 (58% vs 43%, respectively) that was weakly associated with clinical response at 12 weeks (Harper-Wynne et al 2002). In the recently reported IMPACT trial, the neoadjuvant use of tamoxifen versus the third-generation aromatase inhibitor anastrozole versus the combination was compared in 330 postmenopausal patients with primary ER-positive breast cancer (Dowsett et al 2005).…”

Section: Presurgical Biomarker Studies Of Endocrine/sti Therapymentioning

confidence: 99%

Clinical trials of intracellular signal transductions inhibitors for breast cancer — a strategy to overcome endocrine resistance

Johnston

2005

Endocr Relat Cancer

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Acquired resistance to endocrine therapy in breast cancer is associated with an increase in peptide growth factor signaling that results in cross-talk activation of the estrogen receptor (ER). Small molecule signal transduction inhibitors (STIs) can target components of these intracellular pathways, and may prove effective in anticancer therapy. However, early phase II clinical trials with various STIs as monotherapy in advanced breast cancer have shown only a modest level of efficacy for these intracellular inhibitors. Preclinical data suggest that combinations of tamoxifen with STIs may provide significantly greater growth inhibition than either therapy alone, and, furthermore, may delay the emergence of endocrine resistance. There are now several trials assessing the efficacy of combinations of small molecule tyrosine kinase inhibitors (TKIs), such as gefitinib and lapatinib, with either tamoxifen or aromatase inhibitors both in the second-line, endocrine-resistant and first-line, hormone-sensitive setting. Similar trials continue with both farnesyltransferase inhibitors (FTIs) and mTOR antagonists, where there are strong preclinical data to suggest additive or synergistic effects for either of these agents in combination with endocrine therapies. Biomarker studies in the presurgical setting are also being utilized as an alternative approach to investigate whether combined endocrine/STI therapy is an effective clinical strategy. This article reviews some of the preclinical evidence supporting this strategy, together with the current status of clinical trials in this area. Endocrine-Related Cancer (2005) 12 S145-S157

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Comparison of the Systemic and Intratumoral Effects of Tamoxifen and the Aromatase Inhibitor Vorozole in Postmenopausal Patients With Primary Breast Cancer

Abstract: The correlation with vorozole of Ki67 with volume and clinical response supports this as an intermediate marker. The nonsignificant effects on bone and lipid metabolism by the aromatase inhibitor may be important to consider for adjuvant and potential prevention strategies.

Cited by 58 publications

References 39 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

Biological response to hormonal manipulation in oestrogen receptor positive ductal carcinoma in situ of the breast

Clinical trials of intracellular signal transductions inhibitors for breast cancer — a strategy to overcome endocrine resistance

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