Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment

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Abstract

Background:

Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment.

Methods:

Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by ultrasonography. Surgical specimens and corresponding biopsy samples were used for immunohistochemistry. Snap-frozen specimens were also available in a subset of cases, and used for hormone assays and microarray analysis.

Results:

Intratumoral oestrogen levels were significantly lower in DCIS treated with letrozole compared with that in those without the therapy. A great majority of oestrogen-induced genes showed low expression levels in DCIS treated with letrozole by microarray analysis. Moreover, letrozole treatment reduced the greatest dimension of DCIS, and significantly decreased Ki-67 and progesterone receptor immunoreactivity in DCIS tissues.

Conclusion:

These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors potently inhibit oestrogen actions in postmenopausal ER-positive DCIS through rapid deprivation of intratumoral estrogens.

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Most cited references 31

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Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.

Valérie-Jeanne Bardou, Grazia Arpino, Richard Elledge … (2003)

To determine whether progesterone receptor (PgR) status provides additional value to estrogen receptor (ER) status and improves prediction of benefit from endocrine treatment among patients with primary breast cancer. Clinical outcomes of patients in two large databases were analyzed as a function of steroid receptor status. The first database (PP), contained 3,739 patients who did not receive any systemic adjuvant therapy and 1,688 patients who received adjuvant endocrine therapy but no chemotherapy. The second database (SPORE), contained 10,444 patients who received adjuvant endocrine therapy but no chemotherapy. Biochemical ER and PgR assays were identically performed in two different central laboratories. In univariate and multivariate analyses, the prognostic significance of PgR status among systemically untreated patients is modest. Among endocrine-treated patients, however, multivariate analyses, including lymph-node involvement, tumor size, and age, demonstrate that PgR status is independently associated with disease-free and overall survival. For recurrence, the reduction in relative risk (RR) was 25% for ER-positive/PgR-negative patients and 53% for ER-positive/PgR-positive patients, compared with ER-negative/PgR-negative patients (P <.0001, PP patients). Patients with ER-positive/PgR-negative tumors have a reduction in RR of death of 30% (SPORE patients) and 38% (PP patients), compared with patients with ER-negative/PgR-negative tumors (P <.0001). For ER-positive/PgR-positive tumors, the reduction of the risk of death was greater than 46% in SPORE patients and 58% in PP patients, indicating that ER-positive/PgR-positive patients derive more benefit from endocrine therapy (P <.0001). When accurately measured, PgR status is an independent predictive factor for benefit from adjuvant endocrine therapy. Therefore, PgR status should be taken into account when discussing RR reductions expected from endocrine treatment with individual patients.

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Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer.

Mitch Dowsett, Ian Smith, Stephen Ebbs … (2007)

Tumor expression of the proliferation antigen Ki67 is widely used to assess the prognosis of cancer patients. A change in the expression of Ki67 after short-term exposure of patients to therapeutic agents is frequently used as a pharmacodynamic marker of efficacy, particularly among breast cancer patients before undergoing surgery. To determine the clinical significance of the level of tumor cell proliferation during endocrine therapy for breast cancer, we measured the expression of Ki67 in tumor biopsy samples taken before and after 2 weeks of presurgical treatment with anastrozole or tamoxifen or the combination of anastrozole plus tamoxifen in 158 patients with hormone receptor-positive primary disease. In a multivariable analysis, we found that higher Ki67 expression after 2 weeks of endocrine therapy was statistically significantly associated with lower recurrence-free survival (P = .004) whereas higher Ki67 expression at baseline was not. Larger baseline tumor size and lower estrogen receptor level after 2 weeks of treatment were also statistically significantly associated with poorer recurrence-free survival (P < .001 and P = .04, respectively). Our data indicate that measurements of tumor Ki67 level after short-term endocrine treatment may improve the prediction of recurrence-free survival by integrating the prognostic value of Ki67 level at baseline with changes in Ki67 level that are associated with treatment benefit.

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Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype.

Jonna Frasor, Jeanne Danes, Barry Komm … (2003)

Estrogens are known to regulate the proliferation of breast cancer cells and to alter their cytoarchitectural and phenotypic properties, but the gene networks and pathways by which estrogenic hormones regulate these events are only partially understood. We used global gene expression profiling by Affymetrix GeneChip microarray analysis, with quantitative PCR verification in many cases, to identify patterns and time courses of genes that are either stimulated or inhibited by estradiol (E2) in estrogen receptor (ER)-positive MCF-7 human breast cancer cells. Of the >12,000 genes queried, over 400 showed a robust pattern of regulation, and, notably, the majority (70%) were down-regulated. We observed a general up-regulation of positive proliferation regulators, including survivin, multiple growth factors, genes involved in cell cycle progression, and regulatory factor-receptor loops, and the down-regulation of transcriptional repressors, such as Mad4 and JunB, and of antiproliferative and proapoptotic genes, including B cell translocation gene-1 and -2, cyclin G2, BCL-2 antagonist/killer 1, BCL 2-interacting killer, caspase 9, and TGFbeta family growth inhibitory factors. These together likely contribute to the stimulation of proliferation and the suppression of apoptosis by E2 in these cells. Of interest, E2 appeared to modulate its own activity through the enhanced expression of genes involved in prostaglandin E production and signaling, which could lead to an increase in aromatase expression and E2 production, as well as the decreased expression of several nuclear receptor coactivators that could impact ER activity. Our studies highlight the diverse gene networks and metabolic and cell regulatory pathways through which this hormone operates to achieve its widespread effects on breast cancer cells.

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Author and article information

Journal

Journal ID (nlm-ta): Br J Cancer

Journal ID (iso-abbrev): Br. J. Cancer

Title: British Journal of Cancer

Publisher: Nature Publishing Group

ISSN (Print): 0007-0920

ISSN (Electronic): 1532-1827

Publication date (Print): 09 July 2013

Publication date (Electronic): 11 June 2013

Volume: 109

Issue: 1

Pages: 100-108

Affiliations

[1 ]Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine , 2-1 Seiryo-machi, Aoba-ku, 980-8575 Sendai, Japan

[2 ]Department of Surgical Oncology, Tohoku University Graduate School of Medicine , 2-1 Seiryo-machi, Aoba-ku, 980-8575 Sendai, Japan

[3 ]Department of Anatomic Pathology, Tohoku University Graduate School of Medicine , 2-1 Seiryo-machi, Aoba-ku, 980-8575 Sendai, Japan

[4 ]Department of Surgery, Tohoku Kosai Hospital , 2-3-11 Kokubun-cho, Aoba-ku, 980-0803 Sendai, Japan

[5 ]Department of Breast Oncology, Miyagi Cancer Center Hospital , Medeshimashiote, 47-1 Nodayama, 981-1239 Natori, Japan

[6 ]Department of Surgery, Nihonkai General Hospital , 30 Akiho, 998-8501 Sakata, Japan

[7 ]Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine , 2-1 Seiryo-machi, Aoba-ku, 980-8575 Sendai, Japan

[8 ]Department of Pathology, Tohoku University Hospital , Aoba-ku, 1-1 Seiryo-machi, 980-9574 Sendai, Japan

Author notes

[* ]E-mail: t-suzuki@ 123456patholo2.med.tohoku.ac.jp

Article

Publisher Item ID: bjc2013284

DOI: 10.1038/bjc.2013.284

PMC ID: 3708565

PubMed ID: 23756858

SO-VID: 1304abf1-3f4e-42c2-b5bf-e95553fa1002

License:

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

History

Date received : 15 March 2013

Date revision received : 12 May 2013

Date accepted : 15 May 2013

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Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment

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Abstract

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Karger: Gastroenterology

Most cited references 31

Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.

Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer.

Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype.

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