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Old 12-10-2009, 01:09 AM   #1
Rich66
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Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
ER+ issues





(less response to chemo?, synergy, older cyclophosph better for ER+?, plasma estradiol levels test as predictor, low cyclin E bad-CDK2 inhibs reverses issue, genistein (soy) still bad in ER/Her2+, resistance through IGF and EGF receptors, ER subtypes, Hi dose anti-estrogens in ER-, EGFR inhibitors)






Matthew J Ellis: Endocrine therapy specialist
Areas of Research Interest
Insulin-like growth factor signaling and breast cancer, endocrine therapy for breast cancer, signal transduction therapy for breast cancer, preoperative systemic therapy for breast cancer, array based analysis of breast cancer gene expression, breast cancer clinical trial correlative science.

Center for Advanced Medicine
Siteman Cancer Center
4921 Parkview Place, A , 7
St. Louis, MO 63110
314-747-1171
Fax: 314-362-7086
Correspondence: Matthew Ellis, M.D., Ph.D., F.R.C.P., Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8056, Division of Oncology, St. Louis, Missouri 63110, USA. Telephone: 314-362-8866; Fax: 314-362-7086; e-mail: mellis@im.wustl.edu





http://jco.ascopubs.org/cgi/content/full/27/33/5492

EDITORIALS

How to Treat Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Amplified Breast Cancer

Javier Cortes Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
José Baselga
Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital; and Universitat Autonoma de Barcelona, Barcelona, Spain
Breast cancer is a heterogeneous disease composed of different molecular subtypes on the basis of gene expression profiling; these subtypes are increasingly being used to estimate clinical outcomes and choose therapeutic options. The molecular subgroups are in great part defined by the expression status of hormone receptors (HRs) and human epidermal growth factor receptor 2 (HER2).1,2 However, HR and HER2 coexpression is not uncommon in breast cancer; approximately half of breast cancers with HER2 overexpression also coexpress HRs. How these tumors behave and, more importantly, how they respond to a variety of therapies are clinical questions that have been only partially addressed to date. Although HR positivity predicts efficacy of endocrine agents in breast cancer, preclinical and clinical data strongly suggest that HER2 overexpression confers intrinsic resistance to hormonal treatment even in the presence of HRs.35 In addition, HER2 overexpression is an independent adverse prognostic factor for breast cancer regardless of the hormonal status of the tumor, suggesting that HR-positive/HER2-positive breast tumors may be too aggressive to derive benefit from single-agent hormonal therapy. These observations have provided a strong rationale for exploring combined anti-HR and anti-HER2 therapies in HR-positive/HER2-positive breast cancer. HER2-targeted strategies in preclinical models have shown therapeutic potential to subvert endocrine resistance in HR-positive/HER2-positive breast cancer.6


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In this issue of Journal of Clinical Oncology, the awaited results of two large randomized first-line clinical trials of the combination of aromatase inhibitors (AIs) with anti-HER2 therapies in patients with advanced HER2-positive breast cancer are published.7,8
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The results of these two studies provide additional evidence, if any was needed, that anti-HER2 therapy should be the backbone of therapy in HER2-positive breast cancer, including for those tumors that coexpress HRs, because they are partially resistant to hormonal therapy. However, a more difficult question to address is whether dual hormonal and anti-HER2 therapy may be used instead of the approved chemotherapy and anti-HER2 combinations in advanced HER2-positive breast cancer.1315 The addition of chemotherapy to anti-HER2 therapies in the first-line setting results in an overall higher clinical benefit rate, including higher RRs and time to disease progression.
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in this patient population, direct comparisons between hormonal therapy and chemotherapy HER2-based combinations are not available
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Although the question remains unanswered, it would seem good clinical judgment to continue to preferentially use chemotherapy in combination with anti-HER2 therapy in this patient population, especially in those situations in which a rapid response is needed or the tumor is progressing rapidly. However, it is also apparent from the studies presented here that the combination of hormonal plus anti-HER2 therapy is a valid option that should be considered in those patients with increased frailty or with less aggressive clinical course of disease.
Quote:
In summary, the studies by Kaufman et al7 and Johnston et al8 establish the importance of blocking the HER2 receptor with trastuzumab or lapatinib in patients with metastatic breast cancer and HR and HER2 coexpression. As for the clinical implications of these studies, although combined chemotherapy and anti-HER2 therapy will remain the treatment of choice at this time, the combination of anti-HER2 and hormonal therapy is a valid option that expands the available choices for this patient population and should be considered in individualized clinical settings. Furthermore, these two studies open the gate to future studies to revert resistance to hormonal therapy and to combinations of multiple anti-HER2–based approaches that will, it is hoped, eliminate or reduce the need for cytotoxic-based therapy in this patient population. For all these reasons, the two studies should be viewed as pioneering and hypothesis driven; they are likely to become obligatory references in the field of HER2 breast cancer.
Expert Rev Anticancer Ther. 2009 Nov;9(11):1549-57.
Lapatinib plus letrozole for postmenopausal patients with advanced HER2(+)/HR(+) breast cancer.

Guarneri V.
Department of Oncology Hematology and Respiratory Diseases, University of Modena and Reggio Emilia University Hospital, Modena, Italy. guarneri.valentina@unimore.it
Lapatinib is an oral, small-molecule dual inhibitor of human EGF receptor 1 (EGFR/erbB1) and 2 (HER2/erbB2). Lapatinib has recently been approved, in combination with capecitabine, for the treatment of HER2-positive metastatic breast cancer patients failing trastuzumab therapy. Data from clinical trials are consistently showing the key role of this agent in the management of HER2-positive disease. Moreover, interesting data are suggesting a key role of lapatinib in enhancing endocrine responsiveness and/or restoring endocrine sensitivity in hormone receptor-positive disease. The present article will summarize the main data leading to the clinical development of the combination of lapatinib and the aromatase inhibitor letrozole.

PMID: 19895239 [PubMed - in process]



http://annonc.oxfordjournals.org/cgi/reprint/20/7/1157
What is the role of chemotherapy in estrogen receptor positive, advanced breast cancer?

FULL TEXT

C. H. Barrios1*, C. Sampaio2, J. Vinholes3 & R. Caponero4
1Cancer Institute, Ma˜e de Deus Hospital and PUCRS Faculty of Medicine, Porto Alegre; 2AMO Clinic, Salvador; 3Oncology Clinic of Porto Alegre, Porto Alegre; 4Medical Oncology Clinic, Sao Paulo, Brazil
Received 6 July 2008; revised 5 November 2008; accepted 19 November 2008

Most breast tumors depend on female sex hormones for development and growth, thus being amenable to endocrine therapies. In the management of estrogen receptor (ER)-positive, advanced breast cancer, conventional wisdom dictates the use of endocrine therapy for patients with good prognostic features, whereas chemotherapy is recommended for the treatment of visceral crisis. There is, however, considerable uncertainty regarding the best initial strategy for patients with poor prognostic features other than visceral crisis, such as small-volume visceral involvement and a short disease-free interval after adjuvant therapy. In this article, we examine the role of chemotherapy in ERpositive, advanced breast cancer.

Our review of the literature suggests that, in the absence of visceral crisis, endocrine agents should always be considered a major option for the initial treatment of ER-positive, metastatic breast cancer due to their proven efficacy and favorable toxicity profile. Although certain chemotherapy agents can induce higher response rates and more rapid responses, which are desirable effects in particular situations, the up-front use of chemotherapy does not seem to influence the overall outcome of the disease. In the subset of patients with epidermal growth factor type 2-positive disease, on the other hand, current data still do not support the use of endocrine agents alone.

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It is very important to recognize that the simple presence of visceral metastasis should not be considered definitive indication for chemotherapy, as many patients may present with small-volume liver or lung disease with very little clinical manifestations and be adequate candidates for endocrine strategies.

http://www3.interscience.wiley.com/c...79448/PDFSTART

Commentary on above: LINK

Quote:
Generally speaking, advanced breast cancer patients are broken down into: (1) ER-negative cases that receive chemotherapy 17; (2) HER-2 positive patients who receive trastuzumab combined with chemotherapy, especially since they tend to be less responsive to endocrine therapy 17, 18; (3) ER-positive patients that do not show any poor prognostic features who are given endocrine therapy upfront 5, 17; (4) ER-positive patients with poor prognostic factors that receive chemotherapy upfront.17

In clinical practice, visceral metastasis is usually the decision point in the management of metastatic breast cancer. Barrios et al identify a category of patients with poor prognostic factors that may benefit from first line endocrine therapy. Interestingly, this would include patients with visceral metastasis but not as he names it, visceral crisis, such as those with small volume liver or lung disease and patients with few or no symptoms. The rationale being that chemotherapy does not seem to influence overall survival in these patients and treatment-related toxicity is unwarranted.1
I personally recall treating a 50 year old breast cancer patient presenting radiologically with multiple liver metastases but without any symptoms.
Initially she was given the appropriate chemotherapy regimen but failed to show a radiological response after four cycles. Given her relatively long history, we felt we had run out of chemotherapy options and the decision was to give letrozole a chance. Letrozole was a relatively new drug at the time, not yet approved in the adjuvant setting; therefore, the patient had not received the drug previously. She underwent a dramatic response which was both rapid and durable with a better quality of life when compared to her previous course of chemotherapy. It’s not every day that you get a nice surprise in the practice of oncology and this one was particularly memorable.
Not all ER-positive patients respond so completely, but this story emphasizes the need to justify prescribing chemotherapy in asymptomatic patients when a clear benefit in outcome is doubtful. This brings to mind the recent discovery that endocrine positive tumors can belong to one of two genetic categories (luminal A or luminal B)19, 20, which have different prognostic implications, and would explain why some ER positive patients respond to endocrine therapy more dramatically than others.19, 20
At this stage I would like to emphasize a point that’s not always mentioned in conferences or apparent in Kaplan–Meier survival curves. While only a handful of agents have shown a survival benefit for metastatic breast cancer21, for the patient with life threatening visceral crisis the story is very different. For these individual patients there is a survival benefit. The rapid regression that may be observed with successful chemotherapy could be a life saving decision. A long time ago some colleagues used the term “emergency chemotherapy” to refer to chemotherapy that is administered in an emergency situation aimed at saving lives.22 This is clinically significant, for the individual patient who can tolerate a chemotherapy regimen that is expected to incur a rapid tumor regression and alleviate potentially fatal symptoms. One such example would be the treatment of lymphangitis carcinomatosa, where therapy is a race against time.
Another important point that should be mentioned here is the recent discovery that ER positive tumors have a reduced sensitivity to chemotherapy in both the adjuvant23-26 and neoadjuvant settings.27-30 This article elegantly casts doubt on the evidence that these findings may be extrapolated to the metastatic setting, citing the inadequacy of available trials comparing chemotherapy outcome in ER positive versus ER negative disease.1

Conclusion

This article touches on some very important aspects in our understanding of the role played by chemotherapy and endocrine therapy in the treatment of endocrine positive advanced breast cancer. Clearly, chemotherapy is not for everyone especially asymptomatic patients. In some patients endocrine therapy is associated with similar therapeutic responses compared to chemotherapy and is associated with a better Quality of Life (QoL). Traditionally advanced breast cancer patients with visceral metastasis, shorter time to progression and symptoms are treated with chemotherapy regardless of ER status. The authors of this article identified a category of patients with advanced breast cancer and poor prognostic features that can benefit from endocrine therapy.
Crit Rev Oncol Hematol. 2009 Dec 5. [Epub ahead of print]


Breast Cancer Res Treat. 2008 Nov 23. [Epub ahead of print] Links
Activity of fulvestrant versus exemestane in advanced breast cancer patients with or without visceral metastases: data from the EFECT trial.

Mauriac L, Romieu G, Bines J.
Institut Bergonié, Centre Régional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest, 229 Cours de l'Argonne, 33076, Bordeaux, France, mauriac@bergonie.org.
Purpose Patients with visceral metastases (VM: lung and/or liver metastases) are generally regarded as being less responsive to hormonal therapy, and chemotherapy often becomes the default treatment. This paper reports a subgroup analysis from EFECT (The Evaluation of Faslodex versus Exemestane Clinical Trial) examining the efficacy of fulvestrant and exemestane in patients with or without VM. Methods EFECT is a randomised, double-blind, multicentre, Phase III trial in postmenopausal women with advanced breast cancer progressing or recurring after prior non-steroidal aromatase inhibitor therapy. Results Overall, approximately 57% of patients in EFECT had visceral involvement. Fulvestrant and exemestane demonstrated clinical benefit in 29.1% and 27.2% of patients with VM, respectively. Median duration of response was 13.5 vs 10.8 months and median duration of clinical benefit was 9.9 vs 8.1 months, respectively. Conclusions These results encourage the use of endocrine agents such as fulvestrant in treating patients with advanced breast cancer and VM.
PMID: 19030986 [PubMed - as supplied by publisher




Gan To Kagaku Ryoho. 2009 Dec;36(13):2623-5.
A case of recurrent breast cancer with extensive liver metastasis successfully treated with endocrine therapy

[Article in Japanese]
Kiyoto S, Hara F, Osumi S, Takabatake D, Takashima S, Aogi K, Takashima S.
Dept. of Breast Oncology, Shikoku Cancer Center.
A 56-year-old woman, who underwent breast-conserving surgery and radiation (60 Gy) therapy in July, 1992, at the age of 40, was diagnosed with pT1aN0M0, pStage I. She was administered tamoxifen (TAM) as adjuvant therapy. However, she underwent microdochectomy for DCIS in her contralateral breast in June, 1998. TAM was given till August, 1999. In June, 2006, at the age of 54, 14 years after initial surgery, CT revealed extensive liver masses which were diagnosed as liver metastasis by liver biopsy. Receptor status was positive for ER and PgR, and negative for HER2. AC was started as a first-line chemotherapy ( 4 courses), but did not prove effective. She refused second-line chemotherapy, so letrozole was selected, and subsequently resulted in PR of the liver metastasis. However, 8 months later, with a liver metastasis relapse, exemestane followed by tamoxifen, medroxyprogesterone acetate, and high-dose toremifene were administered sequentially, resulting in long-time disease control. In conclusion, endocrine therapy might be an effective option even in a visceral crisis, if metastatic tumors have showed slow growth and there is positive hormone receptor status.

PMID: 20009467 [PubMed - in process]






Predicting Endocrine Therapy Responsiveness in Breast Cancer (lots of info)

http://www.cancernetwork.com/display.../10165/1376582

Much info but skipping to the all-important conclusion:

Conclusions
Despite the recognition of ER as the best predictive factor for endocrine response, a significant number of patients with ER-positive breast cancer do not benefit from endocrine therapy, and the optimum strategy to predict endocrine responsiveness is yet to be defined. Single markers are unlikely to provide precise outcome predictions. Multigene analysis reflecting tumor proliferation and ER pathway genetic activities analyzed by either IHC (Ki67, ER, PR, HER2) or more sophisticated gene-expression profiling (Oncotype DX, MammaPrint, PAM50) on baseline tumors have added prognostic value and are being tested for their utility in predicting the efficacy of systemic therapy. Promising results have also been obtained with the PEPI score, which incorporates tumor size, lymph node status, and Ki67 and ER expression into a prognostic index that is applied to the surgical sample after a patient has received neoadjuvant endocrine treatment.
One can reasonably conclude from this review that even a minimal 2 to 4 weeks of endocrine therapy before surgery will provide additional information over that obtained from a baseline specimen alone, and a large trial has been activated in the UK to address this hypothesis. Ongoing neoadjuvant studies with correlative endpoints and long-term follow-up are critical in addressing these issues as well as getting us to the next step—a complete mechanistic understanding of the reasons for the success or failure of endocrine treatment, so that new mechanism-based therapeutic approaches can emerge.

This article is reviewed at the following links:
Endocrine Therapy in 2009: Consideration of the Tumor and the Host
Predicting Endocrine Responsiveness: Novel Biomarkers on the Horizon





Tumour markers predictive of successful treatment of breast cancer with primary endocrine therapy in patients over 70 years old: A prospective study.


Stotter A, Walker R.
Breast Surgery, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Groby Road, Leicester, LE3 9QP, UK.
We report a prospective study of women over 70 years of age with early breast cancer who had primary endocrine treatment. Core biopsies of the cancer were taken at diagnosis and assessed using immunohistochemistry for oestrogen receptor (ER), progesterone receptor (PgR), epidermal growth factor receptor (EGFR), pS2, cyclin D1, p21, p53, HER2 and MIB1 (Ki67). Outcome analysis was performed at a median follow-up of 70 months. Correlation was sought between tumour marker measurements and disease control. When all patients were considered, a significant relationship was found between the absence of ER and PgR, the presence of p53 and EGFR, and high MIB1 and treatment failure. However, for the ER positive cancers, no other marker predicted treatment failure or relapse. There remains an important clinical need to identify those ER positive breast cancers that will not respond to endocrine treatment, and those in which the response will be short-lived.



Cancer Res. 2010 Jan 15;70(2):685-96. Epub 2010 Jan 12.
Prognosis of hormone-dependent breast cancers: implications of the presence of dysfunctional transcriptional networks activated by insulin via the immune transcription factor T-bet.

McCune K, Bhat-Nakshatri P, Thorat MA, Nephew KP, Badve S, Nakshatri H.
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Estrogen receptor alpha (ERalpha)-positive breast cancers that co-express transcription factors GATA-3 and FOXA1 have a favorable prognosis. These transcription factors form an autoregulatory hormonal network that influences estrogen responsiveness and sensitivity to hormonal therapy. Disruption of this network may be a mechanism whereby ERalpha-positive breast cancers become resistant to therapy. The transcription factor T-bet is a negative regulator of GATA-3 in the immune system. In this study, we report that insulin increases the expression of T-bet in breast cancer cells, which correlates with reduced expression of GATA-3, FOXA1, and the ERalpha:FOXA1:GATA-3 target gene GREB-1. The effects of insulin on GATA-3 and FOXA1 could be recapitulated through overexpression of T-bet in MCF-7 cells (MCF-7-T-bet). Chromatin immunoprecipitation assays revealed reduced ERalpha binding to GREB-1 enhancer regions in MCF-7-T-bet cells and in insulin-treated MCF-7 cells. MCF-7-T-bet cells were resistant to tamoxifen in the presence of insulin and displayed prolonged extracellular signal-regulated kinase and AKT activation in response to epidermal growth factor treatment. ERalpha-positive cells with intrinsic tamoxifen resistance as well as MCF-7 cells with acquired tamoxifen and fulvestrant resistance expressed elevated levels of T-bet and/or reduced levels of FOXA1 and GATA-3. Analysis of publicly available databases revealed ERalpha-positive/T-bet-positive breast cancers expressing lower levels of FOXA1 (P = 0.0137) and GATA-3 (P = 0.0063) compared with ERalpha-positive/T-bet-negative breast cancers. Thus, T-bet expression in primary tumors and circulating insulin levels may serve as surrogate biomarkers to identify ERalpha-positive breast cancers with a dysfunctional hormonal network, enhanced growth factor signaling, and resistance to hormonal therapy.

PMID: 20068169 [PubMed - in process]



Anticancer Res. 2009 Jun;29(6):2167-71.
Differential effects of aromatase inhibitors and antiestrogens on estrogen receptor expression in breast cancer cells.

Smollich M, Götte M, Fischgräbe J, Radke I, Kiesel L, Wülfing P.
Department of Obstetrics and Gynecology, University of Münster, 48129 Münster, Germany.
BACKGROUND: Estrogen receptors (ER) alpha and beta play an important role in breast cancer. Recently, systemic adjuvant endocrine therapy with selective estrogen receptor modulator (SERM) tamoxifen has been challenged by aromatase inhibitors. Compared to antiestrogens, third-generation aromatase inhibitors (anastrozole and letrozole) exhibit an improved efficacy and tolerability. MATERIALS AND METHODS: Using real-time PCR analysis, 21 breast cancer tissue samples were analysed for a change of the ERalpha/ERbeta ratio during malignant progression. In stimulation experiments, differential effects of SERMs, ER antagonists and aromatase inhibitors have been investigated. RESULTS: Transition from normal breast to grade 1 tumors was characterized by down-regulation of ERbeta (relative quantification [RQ]=0.83, p=0.019), while transition from grade 1 to grade 3 tumors was associated with the decrease of ERalpha expression (RQ=1.14 vs. RQ=0.65, p<0.001). In stimulation assays, tamoxifen and fulvestrant increased ERalpha expression to RQ=1.51 (p=0.01) and RQ=1.42 (p<0.001), respectively, and left ERbeta unchanged. In contrast, aromatase inhibitors up-regulated ERbeta to RQ=1.23 (anastrozole, p=0.029) and RQ=1.38 (letrozole, p=0.048). CONCLUSION: Taken together, data indicate that SERMs/antiestrogens and aromatase inhibitors exhibit opposed effects on the ER expression of breast cancer cells: tamoxifen and fulvestrant up-regulate ERalpha expression, while aromatase inhibitors increase ERbeta expression, which may contribute to the aromatase inhibitors' therapeutic superiority over antiestrogens.

PMID: 19528477 [PubMed - indexed for MEDLINE]





PMID: 19969469 [PubMed - as supplied by publisher]

Cochrane Database Syst Rev. 2009 Oct 7;(4):CD003370.
Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women.

Gibson L, Lawrence D, Dawson C, Bliss J.
Cancer and Public Health Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London, Greater London, UK, WC1E 7HT.
Update of:
BACKGROUND: Endocrine therapy removes the influence of oestrogen on breast cancer cells and so hormonal treatments such as tamoxifen, megestrol acetate and medroxyprogesterone acetate have been in use for many years for advanced breast cancer. Aromatase inhibitors (AIs) inhibit oestrogen synthesis in the peripheral tissues and have a similar tumour-regressing effect to other endocrine treatments. Aminoglutethimide was the first AI in clinical use and now the third generation AIs, anastrozole, exemestane and letrozole, are in current use. Randomised trial evidence on response rates and side effects of these drugs is still limited. OBJECTIVES: To compare AIs to other endocrine therapy in the treatment of advanced breast cancer in postmenopausal women. SEARCH STRATEGY: For this update, the Cochrane Breast Cancer Group Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) and relevant conference proceedings were searched (to 30 June 2008). SELECTION CRITERIA: Randomised controlled trials in postmenopausal women comparing the effects of any AI versus other endocrine therapy, no endocrine therapy, or a different AI in the treatment of advanced (metastatic) breast cancer. Non-English language publications, comparisons of the same AI at different doses, AIs used as neoadjuvant treatment, or outcomes not related to tumour response were excluded. DATA COLLECTION AND ANALYSIS: Data from published trials were extracted independently by two review authors and cross-checked by a third. Hazard ratios (HR) were derived for analysis of time-to-event outcomes (overall and progression-free survival). Odds ratios (OR) were derived for objective response, clinical benefit, and toxicity. MAIN RESULTS: Thirty-seven trials were identified, 31 of which were included in the main analysis of any AI versus any other treatment (11,403 women). No trials were excluded due to inadequate allocation concealment. The pooled estimate showed a significant survival benefit for treatment with an AI over other endocrine therapies (HR 0.90, 95% CI 0.84 to 0.97). A subgroup analysis of the three commonly prescribed AIs (anastrozole, exemestane, letrozole) also showed a similar survival benefit (HR 0.88, 95% CI 0.80 to 0.96). There were very limited data to compare one AI with a different AI, but these suggested an advantage for letrozole over anastrozole.AIs have a different toxicity profile to other endocrine therapies. For those currently prescribed, and for all AIs combined, they had similar levels of hot flushes and arthralgia; increased risks of rash, nausea, diarrhoea and vomiting; but a 71% decreased risk of vaginal bleeding and 47% decrease in thromboembolic events compared with other endocrine therapies. AUTHORS' CONCLUSIONS: In women with advanced (metastatic) breast cancer, aromatase inhibitors including those in current clinical use show a survival benefit when compared to other endocrine therapy.

PMID: 19821307 [PubMed - in process]






Clin Breast Cancer. 2009 Feb;9(1):39-44.
A comparative study of exemestane versus anastrozole in patients with postmenopausal breast cancer with visceral metastases.

Campos SM, Guastalla JP, Subar M, Abreu P, Winer EP, Cameron DA.
Dana-Farber Cancer Institute, Boston, MA, USA. susana_campos@dfci.harvard.edu
PURPOSE: Patients developing visceral breast cancer metastases generally receive chemotherapy rather than endocrine therapy. Recent aromatase inhibitor studies have reported activity in such patients; therefore, this study formally evaluated anastrozole and exemestane in postmenopausal patients in this setting. PATIENTS AND METHODS: Postmenopausal women with advanced breast cancer and > or = 1 visceral (liver or lung) lesion were randomized to anastrozole (1 mg/day orally) or exemestane (25 mg/day orally) for > or = 8 weeks. The primary endpoint was objective response in visceral lesions based on modified Response Evaluation Criteria in Solid Tumors. Secondary endpoints included clinical benefit (objective response plus stable disease > or = 180 days), overall survival, and adverse events. RESULTS: A total of 130 patients were enrolled, and 128 patients (64 anastrozole, 64 exemestane) were included in the intent-to-treat analysis. Accrual delays caused study closure before the target enrollment (N = 200) was reached, limiting the statistical power of the study. Objective response in visceral sites was approximately 15% in both groups. Clinical benefit in visceral sites was 32% of the patients treated with anastrozole and 38% of the patients treated with exemestane. Median survival was 33.3 months and 30.5 months in the anastrozole and exemestane groups, respectively. Toxicities were similar to those previously reported; however, treatment-related adverse events were more frequent with anastrozole (41%) than with exemestane (31%). Both treatments were generally well tolerated in patients with postmenopausal breast cancer with visceral metastases. CONCLUSION: Efficacy was similar in both treatment groups for all endpoints. Aromatase inhibitors can be considered as a treatment option in postmenopausal patients with hormone receptor-positive visceral breast cancer metastases.

PMID: 19299239 [PubMed - indexed for MEDLINE]


Tumori. 2006 Jan-Feb;92(1):13-7.
Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on letrozole or anastrozole. A phase II trial conducted by the Hellenic Group of Oncology (HELGO).

Gennatas C, Michalaki V, Carvounis E, Psychogios J, Poulakaki N, Katsiamis G, Voros D, Kouloulias V, Mouratidou D, Tsavaris N.
Department of Surgery, Areteion Hospital, University of Athens, Greece. gennatas@otenet.gr
AIMS AND BACKGROUND: The understanding of hormonal therapies in postmenopausal women with metastatic breast cancer has advanced greatly in the past several decades. With the introduction of orally active, potent and selective third-generation aromatase inhibitors (anastrozole, letrozole and exemestane), approaches to the treatment of hormone-sensitive advanced breast cancer are undergoing reevaluation. For treatment of advanced or metastatic disease that has progressed on tamoxifen, all three agents are active. The purpose of the study was to assess the antitumor efficacy and tolerance of exemestane administered as third-line hormonal therapy to postmenopausal women with metastatic breast cancer refractory to letrozole and anastrozole. STUDY DESIGN: Sixty postmenopausal women with stage IV hormone receptor-positive carcinoma of the breast were enrolled in the study. All patients had received two prior hormonal manipulations and had measurable or assessable disease. All adverse events were monitored. RESULTS: Objective tumor response was achieved in 12 (20%) patients (95% CI, 9.6-30.4). The overall clinical benefit was 38.3% (95% CI, 21.2-49.3), and the median duration of objective tumor response was 20 months (range, 9-26). The median time to death was 17.4 months (95% CI, 16.14-18.66). CONCLUSIONS: Exemestane represents an active and well-tolerated treatment option in pretreated patients with advanced breast cancer who have received standard first- and second line hormonal therapies. By extending the sequence of hormonal therapy, disease progression and the need for chemotherapy may be significantly delayed.

PMID: 16683378 [PubMed - indexed for MEDLINE]



Cancer Invest. 2007 Mar;25(2):102-5.
Clinical evaluation of the use of exemestane as further hormonal therapy after nonsteroidal aromatase inhibitors in postmenopausal metastatic breast cancer patients.

Carlini P, Michelotti A, Ferretti G, Ricci S, Giannarelli D, Pellegrini M, Cresti N, Di Cosimo S, Bria E, Papaldo P, Fabi A, Ruggeri EM, Milella M, Alimonti A, Salesi N, Cognetti F.
Department of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy. pcarlini@iol.it
OBJECTIVES:The aromatase inhibitors Anastrozole, Letrozole (type 2 nonsteroidal aromatase inhibitors: n-SAI) and Exemestane (type 1 steroidal aromatase inactivator) are used respectively as first- and second-line hormonal therapy in postmenopausal metastatic breast cancer women. Few clinical data are published on the sequential use of different classes of aromatase inhibitors. METHODS: We report an analysis on 30 postmenopausal metastatic breast cancer women treated between January 2000 and May 2002 in 2 Italian Oncology Institutions with the hormonal sequence n-SAI (Anastrozole, Letrozole) --> Exemestane. RESULTS: When receiving n-SAI (Anastrozole 8 patients and Letrozole 22 patients), 1 out of 30 women achieved a partial response, 20 of 30 patients no change (NC) > or =6 months. The analysis of the entire population treated with Exemestane showed an overall clinical benefit (CB) of 46.6 percent (14/30) with a median duration of 12 months (95%CI 6-25) and a median time to progression (TTP) of 4 months (95%CI 1-25). CONCLUSIONS: These data confirm a partial lack of cross-resistance between n-SAI --> Exemestane given in sequence.



Oncology. 2005;69(6):471-7. Epub 2006 Jan 12.
Sequential treatment with exemestane and non-steroidal aromatase inhibitors in advanced breast cancer.

Bertelli G, Garrone O, Merlano M, Occelli M, Bertolotti L, Castiglione F, Pepi F, Fusco O, Del Mastro L, Leonard RC.
South West Wales Cancer Institute, Swansea, United Kingdom. gianfilippo.bertellli@swansea-tr.wales.nhs.uk
BACKGROUND: The steroidal aromatase inactivator exemestane has demonstrated activity after prior failure of non-steroidal aromatase inhibitors (including third-generation inhibitors letrozole and anastrozole) in postmenopausal women with advanced breast cancer. If exemestane is used as first anti-aromatase agent, however, it is unclear whether patients can still benefit from letrozole or anastrozole after progression. PATIENTS AND METHODS: Postmenopausal patients with advanced, hormone receptor-positive or -unknown breast cancer were eligible for this study. Patients with no prior exposure to anti-aromatase drugs received exemestane, 25 mg daily, as first anti-aromatase agent. At the time of progression, patients were crossed-over to anastrozole or letrozole if further endocrine therapy was considered appropriate. Patients with prior exposure to anti-aromatase agents were also included in the study, and were given anastrozole or letrozole if they had previously received exemestane, or exemestane if they had previously received anastrozole or letrozole. The primary endpoint of the study was the clinical benefit rate (complete response + partial response + stabilization of disease for >or=24 weeks). RESULTS: Forty patients received exemestane 25 mg daily as first anti-aromatase agent, with a CB rate of 67.5% (95% CI 52.9-82.0%) and a median time to progression (TTP) of 9.6 months. In 18 patients, letrozole (n = 17) or anastrozole (n = 1) were used after failure of exemestane: the CB rate was 55.6% (95% CI 32.6-78.5%) with a median TTP of 9.3 months. In 23 patients, exemestane was used after failure of letrozole or anastrozole: the CB rate was 43.5% (95% CI 23.2-63.7%) with a median TTP of 5.1 months. CONCLUSIONS: Our study confirms that exemestane is active after prior failure of letrozole or anastrozole. We have also shown that patients can receive exemestane as their first anti-aromatase agent and still benefit from letrozole or anastrozole after progression. This suggests that the partial non-cross resistance between steroidal and non-steroidal anti-aromatase agents is independent of the sequence employed.

PMID: 16410685 [PubMed - indexed for MEDLINE]




Cancer Biol Ther. 2004 May;3(5):460-7. Epub 2004 May 18.
Estrogen receptor expression and sensitivity to paclitaxel in breast cancer.

Dougherty MK, Schumaker LM, Jordan VC, Welshons WV, Curran EM, Ellis MJ, El-Ashry D.
Lombardi Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
Comment in:
A retrospective analysis of CALGB trial 9344 suggested paclitaxel administration following cyclophosphamide and doxorubicin adjuvant chemotherapy is most beneficial for patients with ERalpha negative (ERalpha-) breast cancer. Since the cytotoxic effects of paclitaxel are cell cycle dependent, we postulated that the relationship between ERalpha and the effectiveness of adjuvant paclitaxel reflects the observation that ERalpha positive (ERalpha+) breast cancers proliferate more slowly than ERalpha- breast cancers. Three in vitro models (MCF-7, T47D and ZR-75) were examined to compare growth rates and paclitaxel-induced apoptosis in ERalpha+ and ERalpha- clones of the same, originally ERalpha+ cell line. For the T47D and ZR-75 cell lines, loss of ERalpha was associated with a decrease in doubling time and an increase in paclitaxel sensitivity. However, when cell culture conditions were altered to achieve equivalent cell proliferation rates, no difference in paclitaxel sensitivity was observed. Similarly, an ERalpha- clone of MCF-7 cells that did not exhibit an enhanced growth rate compared to its ERalpha+ counterpart also did not show increased paclitaxel sensitivity. The combined apoptotic effects of tamoxifen and paclitaxel on MCF-7 cells were not synergistic or even clearly additive. In these in vitro models, the effectiveness of paclitaxel correlated more closely with growth rate than ERalpha expression. These data suggest that measurements of tumor proliferation may provide more accurate predictive markers for the benefits of adjuvant paclitaxel than ERalpha analysis.

PMID: 15020841 [PubMed - indexed for MEDLINE]



Int J Oncol. 2009 Feb;34(2):313-9.
Resistance to paclitaxel therapy is related with Bcl-2 expression through an estrogen receptor mediated pathway in breast cancer.

Tabuchi Y, Matsuoka J, Gunduz M, Imada T, Ono R, Ito M, Motoki T, Yamatsuji T, Shirakawa Y, Takaoka M, Haisa M, Tanaka N, Kurebayashi J, Jordan VC, Naomoto Y.
Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, and Department of Surgery, Okayama City Hospital, Okayama 700-8558, Japan.
Taxanes are approved for the treatment of breast cancer that has spread to the lymph nodes, following surgery and doxorubicin containing chemotherapy. Taxanes have improved the survival of breast cancer patients, especially in estrogen receptor (ER) negative population in clinical settings. This time we examined the relationship between chemosensitivity to Taxanes and expresson of ERalpha in breast cancer cell lines. In vitro effects of paclitaxel in 4 ER-positive and 3 ER-negative breast cancer cell lines were investigated by MTT assay. We also investigated members of Bcl-2 family by Western blotting and RT-PCR to clarify their role in paclitaxel resistance both in ER-positive and in ER-negative cells. ER-negative cell lines were more sensitive to paclitaxel than ER-positive cells. ER-negative KPL-4 and ZR-75-30 cells, which were sensitive to paclitaxel, became resistant when they were treated with demethylation agent, 5-aza-2'-deoxycytidine. Analysis of proapoptotic (Bax) and antiapoptotic (Bcl-2) molecules suggested that Bcl-2 is likely to have a role in the resistance of ER-positive cells. Bcl-2 expression was increased in a time-dependent manner after treatment of ER-positive cell lines with estrogen (E2). On the other hand, Bcl-2 was not detected in ER-negative cell lines. However, no significant difference was detected for Bax mRNA levels before and after E2 treatment in ER-positive and negative cell lines. Activation of ER gene expression in ER-negative KPL-4 cells by 5-aza-2'-deoxycytidine resulted in up-regulation of Bcl-2 mRNA. To support our data, we examined paclitaxel sensitivity in ER-negative MDA-MB-231 and ER stable transfectant cells S30 and JM6. This experiment also showed ER-negative cells were sensitive to paclitaxel but ER-positive cells were resistant to it. These results suggest that ER influenced chemosensitivity to paclitaxel through regulation of Bcl-2 family and regulation of the pathway may be crucial to increase the efficacy of taxanes in ER-positive breast cancer.

PMID: 19148464 [PubMed - indexed for MEDLINE]






Breast. 2007 Jun;16(3):323-5. Epub 2007 Feb 9.
Potential benefit of maintenance trastuzumab and anastrozole therapy in male advanced breast cancer.

Carmona-Bayonas A.
Department of Medical Oncology and Haematology, Hospital Universitario Morales Meseguer, Murcia, Spain. trebla_albert@hotmail.com
Less than 1% of breast cancers occur in males, and the optimal hormonal therapy in this setting is unknown. Tamoxifen is effective in this entity, but unfortunately there is little information on aromatase inhibitors (AI) or fulvestrant. It has been suggested that the association of AI and GnRh analogues and AI could block the two routes of oestrogen production in males, and therefore this approach could increase efficacy. However, it could also enhance the rate of adverse events (hot flashes, sexual impotence, etc.). In this report we report 11 months of progression-free survival, without any adverse events, in a patient who received trastuzumab and anastrozole therapy. We conclude that this combination is a reasonable option in men with ER+ and Her2+ advanced breast cancer.

PMID: 17292609 [PubMed - indexed for MEDLINE]




Carcinogenesis. 2010 Jan 12. [Epub ahead of print]
Genistein Induces Enhanced Growth Promotion in ER Positive/erbB-2 Overexpressing Breast Cancers by ER-erbB-2 crosstalk and p27/kip1 Downregulation.

Yang X, Yang S, McKimmey C, Liu B, Edgerton S, Bales W, Archer L, Thor AD.
Department of Pathology, University of Oklahoma Health Sciences Center.
Genistein is a major isoflavone with known hormonal and tyrosine kinase modulating activities. Genistein has been shown to promote the growth of estrogen receptor (ER) positive MCF-7 cells. In ER negative/erbB-2 overexpressing cells, genistein has been shown to inhibit cell growth through its tyrosine kinase inhibitor activity. The effects of genistein on cell growth and tamoxifen response in ER positive/erbB-2 altered breast cancers (known as luminal type B and noted in approximately 10-20% of breast cancers) have not been well explored. Using erbB-2 transfected ER+ MCF-7 cells, we found that genistein induced enhanced cellular proliferation and tamoxifen resistance when compared to control MCF-7 cells. These responses were accompanied by increased phosphorylation of ERalpha and ER signaling, without increase in ER protein levels. Genistein treated MCF-7/erbB-2 cells also showed enhanced activation/phosphorylation of erbB-2, Akt and MAPK/Erk. Blockade of the PI3K and/or MAPK pathways abrogated genistein induced growth promotion, suggesting that genistein effects involve both critical signaling pathways. We also found that p27/kip1 was markedly downregulated in genistein treated MCF-7/erbB-2 cells. Overexpression of p27/kip1 attenuated genistein mediated growth promotion.



In aggregate, our data suggest that the concomitant co-expression of ER and erbB-2 makes breast cancers particularly susceptible to the growth promoting effects of genistein across a wide range of doses. The underlying mechanisms involve enhanced ER-erbB-2 crosstalk and p27/kip1 downregulation.

PMID: 20067990 [PubMed - as supplied by publisher]



Clin Cancer Res. 2004 Oct 1;10(19):6466-75.
Leptin interferes with the effects of the antiestrogen ICI 182,780 in MCF-7 breast cancer cells.

Garofalo C, Sisci D, Surmacz E.
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
PURPOSE: Obesity is a risk factor for breast cancer development in postmenopausal women and correlates with shorter disease-free and overall survival in breast cancer patients, regardless of menopausal status. Adipose tissue is a major source of leptin, a cytokine regulating energy balance and controlling different processes in peripheral tissues, including breast cancer cell growth. Here, we investigated whether leptin can counteract antitumorigenic activities of the antiestrogen ICI 182,780 in breast cancer cells. EXPERIMENTAL DESIGN: Mitogenic response to leptin and the effects of leptin on ICI 182,780-dependent growth inhibition were studied in MCF-7 estrogen receptor alpha-positive breast cancer cells. The expression of leptin receptor and the activation of signaling pathways were studied by Western immunoblotting. The interference of leptin with ICI 182,780-induced estrogen receptor alpha degradation was probed by Western immunoblotting, fluorescence microscopy, and pulse-chase experiments. Leptin effects on estrogen receptor alpha-dependent transcription in the presence and absence of ICI 182,780 were studied by luciferase reporter assays and chromatin immunoprecipitation. RESULTS: MCF-7 cells were found to express the leptin receptor and respond to leptin with cell growth and activation the signal transducers and activators of transcription 3, extracellular signal-regulated kinase-1/2, and Akt/GSK3/pRb pathways. The exposure of cells to 10 nmol/L ICI 182,780 blocked cell proliferation, induced rapid estrogen receptor alpha degradation, inhibited nuclear estrogen receptor alpha expression, and reduced estrogen receptor alpha-dependent transcription from estrogen response element-containing promoters. All of these effects of ICI 182,780 were significantly attenuated by simultaneous treatment of cells with 100 ng/mL leptin. CONCLUSIONS: Leptin interferes with the effects of ICI 182,780 on estrogen receptor alpha in breast cancer cells. Thus, high leptin levels in obese breast cancer patients might contribute to the development of antiestrogen resistance.

PMID: 15475434 [PubMed - indexed for MEDLINE]


Int J Oncol. 2003 Aug;23(2):369-80.
Induction of antiproliferation and apoptosis in estrogen receptor negative MDA-231 human breast cancer cells by mifepristone and 4-hydroxytamoxifen combination therapy: a role for TGFbeta1.

Liang Y, Hou M, Kallab AM, Barrett JT, El Etreby F, Schoenlein PV.
Department of Surgery, Medical College of Georgia, Augusta, GA, USA.
Mifepristone (MIF) is an antiprogestin with potent anti-glucocorticoid and anti-androgen activity. MIF also appears to have anti-tumor activity independent of its ability to bind to nuclear receptors. In this study, we tested the ability of MIF to inhibit the growth of ER and PR negative breast cancer cells. In addition, because high-dose anti-estrogen treatment has been shown to inhibit ER and PR negative breast cancer cells, we compared the anti-proliferative activity of MIF to that of the anti-estrogen 4-hydroxytamoxifen (TAM) or combination hormonal therapy (MIF + TAM). MIF and TAM therapy induced a significant time- and dose-dependent growth inhibition and, ultimately, induced cell death in MDA-231 cells as evidenced by increased DNA fragmentation, cytochrome c release from the mitochondria, and the activation of caspase-3. The anti-proliferative activity of TAM plus MIF combination treatment was at least additive as compared to either monotherapy. The earliest indicator of TAM and MIF cytostatic and cytotoxic action on MDA-231 cells was a significant (p<0.05) induction of TGFbeta1 secretion into the growth medium within 4 h of treatment. Secreted TGFbeta1 levels at 24 and 48 h were significantly higher in the TAM plus MIF treatment group as compared to cells treated with TAM or MIF alone. TGFbeta1 neutralizing antibody or addition of mannose-6-phosphate (M6P), a reagent also used to inhibit TGFbeta1, significantly attenuated the TAM and/or MIF-induced cell growth inhibition and cell death. In summary, our results indicate that MIF used in combination with TAM can effectively kill estrogen-insensitive human breast cancer cells. Our study further implies that agents that effectively increase TGFbeta1 levels in ER negative breast cancer cells may be one treatment approach for hormone-independent breast cancers.

PMID: 12851686 [PubMed - indexed for MEDLINE]


Low-dose estrogen may help if breast cancer recurs

2/10/2010


WASHINGTON - A very low dose of estrogen might help women whose breast cancer has come back after treatment, researchers reported Tuesday.
Even though most treatments are aimed at stopping estrogen from fueling tumors, the researchers said after years of this therapy the body may need some of the hormone to fight them off.
Their findings, published in the Journal of the American Medical Association, suggest a cheap way to help some patients with advanced breast cancer.
Dr. Matthew Ellis of Washington University School of Medicine in St. Louis and colleagues studied 66 women with advanced breast cancer who had been treated with newer drugs called aromatase inhibitors.
They include Pfizer's Aromasin, Novartis's Femara, and AstraZeneca Plc's Arimidex.
"The women in the study had all experienced a relapse while on estrogen-lowering drugs, and their disease was progressing," Ellis said in a statement.
"So they were faced with undergoing chemotherapy. We found that estrogen treatment stopped disease progression in many patients and was much better tolerated than chemotherapy would have been."
They gave the women a form of estrogen called estradiol, in both high and very low doses. Both doses helped 30 per cent of the women, Ellis and colleagues found.
"We demonstrated clearly that the low dose was better tolerated than the high dose and was just as effective for controlling metastatic disease," Ellis said.
The treatment was not always permanent. In 30 per cent of the women helped by the estrogen, the tumors started growing again. But going back on the aromatase inhibitors — a daily pill that is far less toxic than chemotherapy — helped a third of these women.
More than 400,000 women die from breast cancer globally every year. About 75 per cent of breast cancers are estrogen-receptor-positive, meaning they are fed by estrogen, and treatment with drugs such as tamoxifen and the aromatase inhibitors cuts off this supply of hormones.
(Editing by Todd Eastham)
© Copyright (c) Reuters






Cancer Res. 2009 May 1;69(9):3955-62. Epub 2009 Apr 14.
PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer.

Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM, Parker JS, Miller MA, Huntsman DG, Lin L, Snider J, Davies SR, Olson JA Jr, Watson MA, Saporita A, Weber JD, Ellis MJ.
Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Several phosphoinositide 3-kinase (PI3K) catalytic subunit inhibitors are currently in clinical trial. We therefore sought to examine relationships between pharmacologic inhibition and somatic mutations in PI3K catalytic subunits in estrogen receptor (ER)-positive breast cancer, in which these mutations are particularly common. RNA interference (RNAi) was used to determine the effect of selective inhibition of PI3K catalytic subunits, p110alpha and p110beta, in ER(+) breast cancer cells harboring either mutation (PIK3CA) or gene amplification (PIK3CB). p110alpha RNAi inhibited growth and promoted apoptosis in all tested ER(+) breast cancer cells under estrogen deprived-conditions, whereas p110beta RNAi only affected cells harboring PIK3CB amplification. Moreover, dual p110alpha/p110beta inhibition potentiated these effects. In addition, treatment with the clinical-grade PI3K catalytic subunit inhibitor BEZ235 also promoted apoptosis in ER(+) breast cancer cells. Importantly, estradiol suppressed apoptosis induced by both gene knockdowns and BEZ235 treatment. Our results suggest that PI3K inhibitors should target both p110alpha and p110beta catalytic subunits, whether wild-type or mutant, and be combined with endocrine therapy for maximal efficacy when treating ER(+) breast cancer.

PMID: 19366795 [PubMed - indexed for MEDLINE]



Here is the most recent research on pubmed by Rana (maybe explaining benefit of blocking estrogen with chemo in ER+..i.e. chemoendocrine therapy):

Cancer Res. 2010 Feb 15;70(4):1731-40. Epub 2010 Feb 9.
Estrogen Suppresses MLK3-Mediated Apoptosis Sensitivity in ER+ Breast Cancer Cells.

Rangasamy V, Mishra R, Mehrotra S, Sondarva G, Ray RS, Rao A, Chatterjee M, Rana B, Rana A.
Authors' Affiliations: Department of Pharmacology and Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; Department of Pathology, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, Texas; Division of Biochemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India; and Hines Veterans Affairs Medical Center, Hines, Illinois.
Little knowledge exists about the mechanisms by which estrogen can impede chemotherapy-induced cell death of breast cancer cells. 17beta-Estradiol (E(2)) hinders cytotoxic drug-induced cell death in estrogen receptor-positive (ER(+)) breast cancer cells. We noted that the activity of the proapoptotic mixed lineage kinase 3 (MLK3) kinase was relatively higher in estrogen receptor-negative (ER(-)) breast tumors, suggesting that E(2) might inhibit MLK3 activity. The kinase activities of MLK3 and its downstream target, c-Jun NH(2)-terminal kinase, were rapidly inhibited by E(2) in ER(+) but not in ER(-) cells. Specific knockdown of AKT1/2 prevented MLK3 inhibition by E(2), indicating that AKT mediated this event. Furthermore, MLK3 inhibition by E(2) involved phosphorylation of MLK3 Ser(674) by AKT, attenuating the proapoptotic function of MLK3. We found that a pan-MLK inhibitor (CEP-11004) limited Taxol-induced cell death and that E(2) accentuated this limitation. Taken together, our findings indicate that E(2) inhibits the proapoptotic function of MLK3 as a mechanism to limit cytotoxic drug-induced death of ER(+) breast cancer cells. Cancer Res; 70(4); 1731-40.

PMID: 20145118 [PubMed - in process]


Should You Be Scared of Estrogen?


http://www.pomegranatehealth.com/blog/?p=15

In fact pomegranate contains a wider variety of phytoestrogens than any other plant. And one of the phytoestrogens found in pomegranate is another very weak estrogen – 17 alpha-estradiol. This form of estrogen is actually a mirror image of 17 beta-estradiol. But while 17 beta-estradiol is the most potent of estrogens, 17 apha-estradiol is the mildest.
In vitro (laboratory petri dish) studies as well as studies on mice have shown that, indeed, this and other estrogens from pomegranate occupy the ignition switch so stronger estrogens can’t take affect.



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Old 12-11-2009, 07:28 AM   #2
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Re: ER+ issues

I would be very interested in reading the whole article. Does anyone have access to it?

Jacqueline
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Old 12-12-2009, 12:51 AM   #3
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Re: ER+ issues

Video clip from makers of Faslodex on hormonal aspects of BC:
http://www.hormonalaspectsofbc.com/p...211/index.html

Of note is that host says it can take 3 months before effectiveness is shown in hormonal therapy. Tumor can initially enlarge and Markers can rise even when eventually effective.




Older abstract, but maybe still relevant:


Clin Ther. 2005 Nov;27(11):1671-84.
Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer.

Berry J.
MacNeal Cancer Center, 3340 South Oak Park Avenue, Berwyn, IL 60402, USA. jberry@macneal.com
BACKGROUND: Five years of tamoxifen therapy has been the standard of care for the adjuvant treatment of estrogen receptor-positive early-stage breast cancer for many years and was the first hormonal treatment for postmenopausal women with advanced or metastatic disease. The third-generation aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole offer new treatment options, although their efficacy has not been compared directly in randomized, double-blind, controlled trials in any breast cancer treatment setting. OBJECTIVE:: The goal of this article was to review the results of recent randomized, controlled clinical trials of the AIs in the settings of neoadjuvant, adjuvant, and advance d/metastatic breast cancer. METHODS: MEDLINE was searched for descriptions of randomized, controlled clinical trials published from 1990 to 2005 using the terms breast cancer, aromatase, aromatase inhibitor, anastrozole, exemestane, and letrozole. Abstracts from the proceedings of several oncology meetings held between 2001 and 2005 were searched to capture relevant emerging data. RESULTS: In 2 Phase III trials comparing an AI with tamoxifen for the adjuvant treatment of breast cancer in postmenopausal women, disease-free survival was significantly improved with anastrozole and letrozole compared with tamoxifen as initial adjuvant treatment (P = 0.01 and P = 0.003, respectively). A switch to either anastrozole (2 Phase III trials) or exemestane (1 Phase III trial) after 2 to 3 years of adjuvant tamoxifen therapy was more effective in reducing the risk of recurrence than continued tamoxifen therapy (P = 0.006, P < 0.002, and P < 0.001, respectively); data on switching to letrozole are expected soon. In another Phase III trial, letrozole was found to improve disease-free survival in the extended adjuvant setting (P < or = 0.001) and was the only AI consistently more effective than tamoxifen in the neoadjuvant setting. In 3 Phase III studies (1 letrozole vs tamoxifen, 2 anastrozole vs tamoxifen), both anastrozole and letrozole were more efficacious than tamoxifen in the first-line setting, and some patients receiving letrozole had better overall response rates compared with those receiving anastrozole in the second-line setting (19.1% vs 12.3%, respectively; P = 0.013). In a patient-preference study, those receiving letrozole reported fewer adverse events than those receiving anastrozole (43% vs 65%; P < 0.003), and more patients preferred letrozole to anastrozole (68% vs 32%; P < 0.01). CONCLUSIONS: Currently, anastrozole and letrozole are associated with the most complete data over the breast cancer care continuum, with efficacy in early-stage, locally advanced, and metastatic disease. In-direct comparisons suggest stronger evidence for the use of letrozole compared with other AIs for breast cancer in postmenopausal women who require estrogen-deprivation therapy. Data from randomized, double-blind comparative studies will help clarify the differences between AIs.

PMID: 16368441 [PubMed - indexed for MEDLINE]



Hormone sensitivity of breast stem cells presents drug target

Featured In: Disease Research
By EurekAlert Sunday, April 11, 2010




Researchers at the Walter and Eliza Hall Institute have discovered that breast stem cells are exquisitely sensitive to the female hormones oestrogen and progesterone, a finding that opens the way for the development of new preventions and treatments for breast cancer.
The discovery, by scientists in the institute's Stem Cells and Cancer and Bioinformatics divisions, also explains decades of evidence linking breast cancer risk to exposure to female hormones.
It has been published online today in the international journal Nature.
Dr Jane Visvader, who led the research with Dr Geoff Lindeman, said sustained exposure to oestrogen and progesterone was a well-established risk factor for breast cancer. "There is a clear evidence that the more menstrual cycles a woman has the greater her breast cancer risk," Dr Visvader said. "There is even an increase in breast cancer risk in the short-term following pregnancy. However the cellular basis for these observations has been poorly understood."
In the mid-2000s, Drs Visvader and Lindeman discovered breast stem cells in both mice and humans. Unexpectedly, however, they also found that breast stem cells lacked 'receptors' that would allow them to be directly controlled by the female hormones oestrogen and progesterone.

















Now, work by Drs Visvader and Lindeman in collaboration with Drs Marie-Liesse Asselin-Labat, Gordon Smyth and others at the institute, has revealed that despite lacking receptors for oestrogen and progesterone, breast stem cells are still remarkably sensitive to female hormones.
Using mouse models, they showed that when the ovaries were removed or the animals were treated with hormone inhibitors (which are in clinical use as anti-breast cancer agents), breast stem cell numbers dropped and the cells appeared to become dormant.
Dr Lindeman, who is also a medical oncologist at the Royal Melbourne Hospital, said this finding helped to explain why the effects of 'chemoprevention' – a treatment aimed at breast cancer prevention continued long after anti-estrogen tablets have been stopped.

"Our research also revealed that during pregnancy there is a profound increase in breast stem cell numbers," Dr Lindeman said.
"This might account for the short-term increase in cancer risk associated with pregnancy."
Further studies, in collaboration with Dr Jack Martin at St Vincent's Institute Melbourne and Dr Hisataka Yasuda at the Nagahama Institute for Biochemical Science, identified the RANK ligand pathway as the key cell-signalling pathway responsible for the indirect control of breast stem cells in pregnancy.
Dr Lindeman said inhibitors of RANK signalling have been developed and are currently in clinical trials to help maintain bone strength and treat breast cancer that has spread to the bones. "Our discovery suggests that inhibitors of RANK or other stem cell pathways represent possible therapeutic strategies
that could also be investigated as breast cancer prevention agents," Dr Lindeman said.

http://www.biosciencetechnology.com/...lls-presents-/



Breast Cancer Res. 2010;12(3):R43. Epub 2010 Jun 28.
The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells.

Ikeda H, Taira N, Hara F, Fujita T, Yamamoto H, Soh J, Toyooka S, Nogami T, Shien T, Doihara H, Miyoshi S.
Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama-city, Okayama, Japan. yashima_hirokuni@msn.com


FREE TEXT

Abstract

INTRODUCTION: Microtubule-associated protein tau (MAPT) inhibits the function of taxanes and high expression of MAPT decreases the sensitivity to taxanes. The relationship between estrogen receptor (ER) and MAPT in breast cancer is unclear. In this study, we examined the correlation of MAPT expression with the sensitivity of human breast cancer cells to taxanes, and the relationship between ER and MAPT.
METHODS: The correlation between MAPT expression and sensitivity to taxanes was investigated in 12 human breast cancer cell lines. Alterations in cellular sensitivity to taxanes were evaluated after knockdown of MAPT expression. ER expression was knocked down or stimulated in MAPT- and ER-positive cell lines to examine the relationship between ER and MAPT. The cells were also treated with hormone drugs (tamoxifen and fulvestrant) and taxanes.
RESULTS: mRNA expression of MAPT did not correlate with sensitivity to taxanes. However, expression of MAPT protein isoforms of less than 70 kDa was correlated with a low sensitivity to taxanes. Downregulation of MAPT increased cellular sensitivity to taxanes. MAPT protein expression was increased by stimulation with 17-beta-estradiol or tamoxifen, but decreased by ER downregulation and by fulvestrant, an ER inhibitor. The combination of fulvestrant with taxanes had a synergistic effect, whereas tamoxifen and taxanes had an antagonistic effect.
CONCLUSIONS: Expression of MAPT protein isoforms of less than 70 kDa is correlated with a low sensitivity to taxanes in breast cancer cells. ER influences MAPT expression and fulvestrant increases the sensitivity to taxanes in MAPT- and ER-positive breast cancer cells.
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Old 12-13-2009, 02:51 AM   #4
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Re: ER+ issues

J Clin Oncol. 2010 Feb 1. [Epub ahead of print]
Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor-Positive Breast Cancer in Postmenopausal Women.

Dunbier AK, Anderson H, Ghazoui Z, Folkerd EJ, A'hern R, Crowder RJ, Hoog J, Smith IE, Osin P, Nerurkar A, Parker JS, Perou CM, Ellis MJ, Dowsett M.
Royal Marsden Hospital; Breakthrough Breast Cancer Research Centre, Institute of Cancer Research; and Cancer Research United Kingdom Clinical Trials and Statistics Unit, Section of Clinical Trials, Institute of Cancer Research, London, United Kingdom; Lineberger Comprehensive Cancer Center and Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC; and Washington University and Siteman Cancer Center, St Louis, MO.
PURPOSE: To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)-positive breast cancers in postmenopausal women. Materials and METHODS: Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. RESULTS: The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = -0.179; P = .05; and r = -0.389; P = .0005, respectively). CONCLUSION: Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.

PMID: 20124184 [PubMed - as supplied by publisher]




Clin Cancer Res. 2008 May 15;14(10):3070-6.
Tamoxifen and aromatase inhibitors differentially affect vascular endothelial growth factor and endostatin levels in women with breast cancer.

Holmes CE, Huang JC, Pace TR, Howard AB, Muss HB.
Department of Medicine, University of Vermont, Burlington, Vermont, USA. ceholmes@uvm.edu
PURPOSE: Circulating and cellular proangiogenic and antiangiogenic proteins such as vascular endothelial growth factor (VEGF) and endostatin contribute to the local angiogenic balance. We explored the effects of tamoxifen and aromatase inhibitors on concentrations of VEGF and endostatin in plasma, serum, and platelet releasate (induced by platelet activation). EXPERIMENTAL DESIGN: VEGF and endostatin concentrations were measured with a quantitative immunoassay before and after 1 to 5 weeks of treatment in 30 women with breast cancer treated with either tamoxifen (n = 14) or aromatase inhibitors (n = 16). Platelet activation was induced by a thrombin receptor agonist. RESULTS: Tamoxifen therapy resulted in an increase in platelet releasate concentrations of VEGF (P = 0.01) but no change in plasma VEGF. In contrast, aromatase inhibitor therapy did not affect serum, plasma, or platelet releasate VEGF. In univariate analysis, aspirin use attenuated the tamoxifen-associated increase in VEGF in the platelet releasate and decreased serum levels of VEGF (P = 0.03). Aromatase inhibitor therapy resulted in a decrease in serum endostatin concentrations (P = 0.04), whereas plasma concentrations of endostatin tended to be higher during treatment with aromatase inhibitors (P = 0.06). Tamoxifen therapy resulted in no change in serum or plasma endostatin concentrations. Platelet releasate concentrations of endostatin did not change with either treatment. Interindividual variability was noted among both aromatase inhibitor--and tamoxifen-treated patients. CONCLUSIONS: Tamoxifen and aromatase inhibitor therapy affect VEGF and endostatin levels and likely contribute to the angiogenic balance in breast cancer patients. Aspirin decreased the proangiogenic effects of tamoxifen, suggesting that antiplatelet and/or antiangiogenic therapy might improve the effectiveness of tamoxifen in women with breast cancer.

PMID: 18483373 [PubMed - indexed for MEDLINE]





Int J Cancer. 2010 Jan 26. [Epub ahead of print]
Effects of estrogen on breast cancer development: Role of estrogen receptor independent mechanisms.

Yue W, Wang JP, Li Y, Fan P, Liu G, Zhang N, Conaway M, Wang H, Korach KS, Bocchinfuso W, Santen R.
Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908.
Development of breast cancer involves genetic factors as well as lifetime exposure to estrogen. The precise molecular mechanisms whereby estrogens influence breast tumor formation are poorly understood. While estrogen receptor alpha (ERalpha) is certainly involved, non-receptor mediated effects of estradiol (E(2)) may also play an important role in facilitating breast tumor development. A "reductionist" strategy allowed us to examine the role of ERalpha independent effects of E(2) on mammary tumor development in ERalpha knock out (ERKO) mice bearing the Wnt-1 oncogene. Exogenous E(2) "clamped" at early follicular and mid-luteal phase levels (i.e. 80 and 240 pg/ml) accelerated tumor formation in a dose-related fashion in ERKO/Wnt-1 animals (p=0.0002). Reduction of endogenous E(2) by oophorectomy (p<0.001) or an aromatase inhibitor (p=0.055) in intact ERKO/Wnt-1 animals delayed tumorigenesis as further evidence for an ER-independent effect. The effects of residual ERalpha or beta were not involved since enhancement of tumor formation could not be blocked by the anti-estrogen fulvestrant. 17alpha-OH-E(2), a metabolizable but ER-impeded analogue of E(2)stimulated tumor development without measurable uterine stimulatory effects. Taken together, our results suggest that ER-independent actions of E(2) can influence breast tumor development in concert with ER dependent effects. These observations suggest one mechanism whereby aromatase inhibitors, which block E(2) synthesis, would be more effective for breast cancer prevention than use of anti-estrogens which only block ER-mediated effects. (c) 2010 UICC.

PMID: 20104523 [PubMed - as supplied by publisher]



Web address:
http://www.sciencedaily.com/releases/2010/02/
100209131639.htm
Low Forms of Cyclin E Reduce Breast Cancer Drug's Effectiveness

ScienceDaily (Feb. 9, 2010) — Overexpression of low-molecular-weight (LMW-E) forms of the protein cyclin E renders the aromatase inhibitor letrozole ineffective among women with estrogen-receptor-positive (ER+) breast cancers, researchers from The University of Texas M. D. Anderson Cancer Center report in Clinical Cancer Research.
The M. D. Anderson research, led by Khandan Keyomarsi, Ph.D., professor in M. D. Anderson's Department of Experimental Radiation Oncology and the Hubert L. and Olive Stringer Professor in Medical Oncology, found evidence that women whose cancers express the LMW-E are more likely to develop resistance to letrozole. However, their research also showed that treating breast cancer cells with a cyclin-dependent kinase 2 (CDK2) inhibitor can reverse letrozole resistance.
Cyclin E is one of the proteins that regulates the cell cycle, influencing how rapidly a cell passes through the four phases and divides. In tumor cells, cyclin E is converted to low-molecular weight forms, an event that does not occur in normal cells. High levels of LMW-E accelerate the cell's transition through the G1phase, an important checkpoint that can arrest the cell cycle if DNA damage is detected. Elevated levels of LMW-E have been linked to uncontrolled cell proliferation and a poor outcome in breast cancer patients.
Outwitting Drug Resistance

Keyomarsi estimated that approximately 70 percent of all breast cancer patients are estrogen receptor positive (ER+), of which a large percentage are post-menopausal, and would thereby be a candidate to receive an aromatase inhibitor as maintenance therapy. Aromatase inhibitors can reduce the risk of early metastasis among postmenopausal women with ER+ breast cancer. However, not every patient responds to aromatase inhibitors, and those who do will develop resistance to the drugs over time, explained Keyomarsi. Understanding the mechanisms behind this resistance has been a long-standing goal in breast cancer research.
The M. D. Anderson team hypothesized that ER+ breast cancer patients whose tumors express the LMW forms of cyclin E would be less responsive to treatment with an aromatase inhibitor. To test their hypothesis, the researchers exposed aromatase-overexpressing MCF-7/Ac1 breast cancer cells to the full-length form of cyclin E or to the LMW-E forms ("low forms").
"We found that we could negate the growth inhibitory effects of letrozole with the low forms of cyclin E but not with the wild-type cyclin E," said Keyomarsi, the study's senior author. "The mechanism behind this is that the low forms of cyclin E increase the activity of the cyclin E complex, and this complex is what mediates the negative effects."




CDK2 Inhibitor Restores Letrozole's Growth Inhibition

After confirming that the LMW forms of cyclin E suppress the anti-proliferative effects of letrozole, the researchers examined whether a CDK2 inhibitor could reverse the drug resistance in the unresponsive breast cancer cells.
"We challenged the aromatase-overexpressing cells with either the wild-type or the low forms of cyclin E and then treated them with the CDK2 inhibitor roscovitine," Keyomarsi said. "When we did that, we could kill all the cells."
The researchers also looked back at the results of another ongoing study from their group in which 128 ER+ breast cancer patients were treated with an aromatase inhibitor. "Of those, 100 expressed normal levels of wild-type cyclin E, and 28 overexpressed the low forms," Keyomarsi said. "When we looked at recurrence, three of the hundred with wild-type cyclin E had experienced a recurrence compared to four of the twenty-eight with the low forms. That in itself tells us there is a huge difference between the two groups of patients based on the pattern of expression of normal versus low forms of cyclin E."
Of the seven patients who had a recurrence, six had high levels of cyclin E activity. Keyomarsi noted that these patients can be treated with a CDK2 inhibitor, which is now clinically available.
"I believe that in the very near future we will be able to take advantage of the knowledge we now have about the low forms of cyclin E, and identify the patients who have these forms and devise a personalized treatment," Keyomarsi added.
This research was supported by National Institutes of Health grant CA87458 and National Cancer Institute grant P50CA116199, as well as funds from the Clayton Foundation.
Keyomarsi's co-authors on the all-M. D. Anderson study include: Said Akli, Ph.D., Tuyen Bui, Anna Biernacka, M.D. all of the Department of Experimental Radiation Oncology; Kelly K. Hunt, M.D.; and Hannah Wingate, Ph.D., Department of Surgical Oncology; Stacy Moulder, M.D., Department of Breast Medical Oncology; and Susan L. Tucker, Ph.D., Department of Bioinformatics and Computational Biology.






JAMA. 2009 Dec 9;302(22):2437-43.
Soy food intake and breast cancer survival.

Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W.
Department of Medicine, Vanderbilt Epidemiology Center, 2525 West End Ave, Ste 600, Nashville, TN 37203-1738, USA. xiao-ou.shu@vanderbilt.edu
Comment in:
CONTEXT: Soy foods are rich in isoflavones, a major group of phytoestrogens that have been hypothesized to reduce the risk of breast cancer. However, the estrogen-like effect of isoflavones and the potential interaction between isoflavones and tamoxifen have led to concern about soy food consumption among breast cancer patients. OBJECTIVE: To evaluate the association of soy food intake after diagnosis of breast cancer with total mortality and cancer recurrence. DESIGN, SETTING, AND PARTICIPANTS: The Shanghai Breast Cancer Survival Study, a large, population-based cohort study of 5042 female breast cancer survivors in China. Women aged 20 to 75 years with diagnoses between March 2002 and April 2006 were recruited and followed up through June 2009. Information on cancer diagnosis and treatment, lifestyle exposures after cancer diagnosis, and disease progression was collected at approximately 6 months after cancer diagnosis and was reassessed at 3 follow-up interviews conducted at 18, 36, and 60 months after diagnosis. Annual record linkage with the Shanghai Vital Statistics Registry database was carried out to obtain survival information for participants who were lost to follow-up. Medical charts were reviewed to verify disease and treatment information. MAIN OUTCOME MEASURES: Total mortality and breast cancer recurrence or breast cancer-related deaths. Cox regression analysis was carried out with adjustment for known clinical predictors and other lifestyle factors. Soy food intake was treated as a time-dependent variable. RESULTS: During the median follow-up of 3.9 years (range, 0.5-6.2 years), 444 deaths and 534 recurrences or breast cancer-related deaths were documented in 5033 surgically treated breast cancer patients. Soy food intake, as measured by either soy protein or soy isoflavone intake, was inversely associated with mortality and recurrence. The hazard ratio associated with the highest quartile of soy protein intake was 0.71 (95% confidence interval [CI], 0.54-0.92) for total mortality and 0.68 (95% CI, 0.54-0.87) for recurrence compared with the lowest quartile of intake. The multivariate-adjusted 4-year mortality rates were 10.3% and 7.4%, and the 4-year recurrence rates were 11.2% and 8.0%, respectively, for women in the lowest and highest quartiles of soy protein intake. The inverse association was evident among women with either estrogen receptor-positive or -negative breast cancer and was present in both users and nonusers of tamoxifen. CONCLUSION: Among women with breast cancer, soy food consumption was significantly associated with decreased risk of death and recurrence.

PMID: 19996398 [PubMed - in process]

NOTE!!! Soy is still questionable in Her2+(see above)..and Her2 status can change


Environ Health Perspect. 2002 Dec;110 Suppl 6:925-9.
Problems for risk assessment of endocrine-active estrogenic compounds.

Safe SH, Pallaroni L, Yoon K, Gaido K, Ross S, McDonnell D.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466, USA. ssafe@cvm.tamu.edu


Estrogenic industrial compounds such as bisphenol A (BPA) and nonylphenol typically bind estrogen receptor (ER) alpha and ERBeta and induce transactivation of estrogen-responsive genes/reporter genes, but their potencies are usually greater than or equal to 1,000-fold lower than observed for 17Beta-estradiol. Risk assessment of estrogenic compounds on the basis of their potencies in simple reporter gene or binding assays may be inappropriate. For example, selective ER modulators (SERMs) represent another class of synthetic estrogens being developed for treatment of hormone-dependent problems. SERMs differentially activate wild-type ERalpha and variant forms expressing activation function 1 (ER-AF1) and AF2 (ER-AF2) in human HepG2 hepatoma cells transfected with an estrogen-responsive complement C3 promoter-luciferase construct, and these in vitro differences reflect their unique in vivo biologies. The HepG2 cell assay has also been used in our laboratories to investigate the estrogenic activities of the following structurally diverse synthetic and phytoestrogens: 4 -hydroxytamoxifen; BPA; 2 ,4 ,6 -trichloro-4-biphenylol; 2 ,3 ,4 ,5 -tetrachloro-4-biphenylol; p-t-octylphenol; p-nonylphenol; naringenin; kepone; resveratrol; and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane. The results show that synthetic and phytoestrogens are weakly estrogenic but induce distinct patterns of ER agonist/antagonist activities that are cell context- and promoter-dependent, suggesting that these compounds will induce tissue-specific (in vivo(ER agonist or antagonist activities. These results suggest that other receptors, such as the aryl hydrocarbon receptor, that also bind structurally diverse ligands may exhibit unique responses in vivo that are not predicted by standard in vitro bioassays.

PMID: 12634121 [PubMed - indexed for MEDLINE]








SABC 2009
Friday, December 11, 2009 7:00 AM
[402] Complete IGF Signaling Blockade by the Dual-Kinase Inhibitor, BMS-754807, Is Sufficient To Overcome Tamoxifen and Letrozole Resistance In Vitro and In Vivo.

Haluska P, Hou X, Huang F, Harrington SC, Greer A, Macedo LF, Brodie A, Evans DB, Carboni JM, Gottardis MM Mayo Clinic, Rochester, MN; Bristol-Myers Squibb Co., Princeton, NJ; University of Maryland, Baltimore, MD; Novartis Pharma AG, Basel, Switzerland

Resistance to hormonal therapy is a clinically unmet need in breast cancer. IGF signaling has been identified as a major mechanism of resistance to hormonal therapy in breast cancer. As components of the IGF signaling pathway are expressed in most breast cancers, the development of IGF-1R monoclonal antibody (mAb) and tyrosine kinase inhibitors (TKI) are active areas of clinical investigations. A key distinction between the mAb and TKIs are their differences in their ability to inhibit the Insulin Receptor (InsR). While targeting the InsR with TKIs may have a theoretical liability of hyperglycemia, targeting only the IGF-1R may have the theoretical liability of incompletely blocking IGF signaling. As InsR isoform A expression, which can transduce IGF-II-mediated proliferation, is higher in breast cancers compared to normal breast tissue, we investigated whether IGF-1R or IGF-1R/InsR inhibition was sufficient for overcoming resistance to hormonal therapy. To determine the optimal combination strategies for clinical investigations, we tested the hypothesis that IGF signaling inhibition could overcome primary (or de novo/intrinsic) and secondary (or acquired/selected) resistance to hormonal therapy. For these studies, we used either hormone therapy-naïve or hormone therapy-resistant variants of the breast cancer model, MCF-7/AC-1, which has been engineered to stably express full-length human aromatase. We employed and compared a novel, potent dual kinase inhibitor of the IGF-1R and InsR, BMS-754807, which is currently in early clinical investigations, with the IGF-1R antibody mAb391. BMS-754807 has been shown to induce apoptosis more potently than mAb391 in Rh41 human rhabdomyosarcoma cells. In vitro, BMS-754807 demonstrated profound synergy in combination with tamoxifen and letrozole (median effect combination index <0.1). In vivo, BMS-754807 enhanced the anti-tumor activity of tamoxifen and letrozole in hormone-naïve tumors and induced regression of tumors resistant to tamoxifen or letrozole when combined with letrozole. This activity was not observed with mAb therapy, which resulted in greater up-regulation of InsR-A and erbB receptor expression and activation. This suggested a greater susceptibility to resistance pathways with mAb therapy. Dual IGF-1R/InsR blockade alone or in combination was tolerated by the animals and has no significant change in glucose homeostasis. Gene expression profiling experiments to compare the difference between the effects of tamoxifen in combination with BMS-754807 and with mAb revealed alternative pathway signaling is one of the potential mechanisms of resistance.
In summary, combined hormonal therapy with BMS-754807 overcomes primary and secondary resistance to tamoxifen and letrozole and was well tolerated. IGF-1R blockade with a mAb alone is insufficient to overcome resistance and induces InsR over-expression. Thus, IGF signaling through either InsR or IGF-1R may be a major mechanism of resistance to hormonal therapy. These data suggest that blockade of IGF-1 and IGF-II from activation of IGF-1R and InsR, with agents such as BMS-754807 have promise in extending the benefits of hormonal therapy in breast cancer.



By Julie Steenhuysen
CHICAGO, Dec 11 (Reuters) - U.S. researchers may have found a way to overcome resistance to hormone-blocking breast cancer drugs, extending the life of treatments that keep the disease in check.
They said the drug Nexavar or sorafenib, made by German drugmaker Bayer (BAYGn.DE) and its development partner Onyx Pharmaceuticals (ONXX.O), helped re-sensitize breast cancer to treatment with aromatase inhibitors, drugs given to post-menopausal women with hormone-sensitive breast cancers.
"Hormone-receptor positive breast cancers eventually become resistant to hormonal therapy," said Dr. Claudine Isaacs of Georgetown University in Washington, who presented her findings at the American Association for Cancer Research's San Antonio Breast Cancer Symposium.
"There has been a great deal of interest in trying to figure out how we might overcome that resistance or stop the cancer cells from figuring out how to circumvent that hormonal therapy," Isaacs said in a telephone interview.
She said Nexavar, a drug approved for liver and kidney cancer, acts on a lot of cancer-related genes and it also acts to inhibit new blood vessels from forming.
The researchers studied the drug in 35 post-menopausal women with advanced breast cancer resistant to treatment with aromatase inhibitors.
Women in the trial, funded with a grant by Bayer, continued to take the aromatase inhibitor, but they also took Nexavar.
"These women all had disease progression. Twenty-three percent of the women in the study had a clinical benefit from it. It means they either had shrinkage of their tumors or it stayed stable," Isaacs said.
Isaacs said the finding suggests the drug somehow circumvents the mechanism used by the cancer to resist the effects of the aromatase inhibitors.
"It puts the brakes on it so it didn't grow for at least six months," she said.
The treatment was not without side effects. Many women in the study developed a rash called hand-foot syndrome, which causes redness, peeling and some tenderness on the palms of the hands and soles of the feet.
It also caused elevated blood pressure in 11 percent of the women, but Isaacs this could be overcome by putting women on blood pressure drugs before taking Nexavar.
She said the findings were strong enough to inspire the drug companies to start a large, late-stage study to see if it has a significant benefit for women.
Aromatase inhibitors include anastrozole, made by AstraZeneca (AZN.L) under the brand name Arimidex, and exemestane, made by Pfizer Inc (PFE.N), under the brand name Aromasin.
Breast cancer is the second-leading cause of cancer death among U.S. women, after lung cancer. It kills 500,000 people globally every year.


LINK
Potential new therapy to re-sensitize breast cancer (Nexavar/Sorafenib)



SABC 2009

67. Targeting Aldose Reductase: A Novel Strategy in Treating Endocrine Resistance Using Combination Therapy


Treating estrogen receptor-positive breast cancer tumors with a combination of fidarestat (an inhibitor of aldose reductase enzyme) and letrozole (an aromatase inhibitor) could delay or stop tumor resistance to endocrine therapy, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium.
"Single agents are less effective," said Rajeshwar Rao Tekmal, Ph.D., professor of obstetrics and gynecology at the University of Texas Health Science Center at San Antonio. "Many tumors develop resistance, so this combination approach could prolong that window when endocrine therapy is effective."
About two-thirds of breast cancer tumors initially are hormone sensitive or estrogen receptor-positive and respond well to endocrine therapy. However, close to half of those tumors develop resistance to endocrine therapy, said Tekmal.
In this preclinical study, researchers treated estrogen receptor-positive tumors already resistant to letrozole with letrozole and fidarestat. As an inhibitor of aldose reductase enzyme, fidarestat blocks the metabolism of glucose in cancer cells.
Together, the combination effectively re-sensitized the cells to letrozole, allowing for effective endocrine therapy and more cell death.
Researchers believe increased glucose metabolism (polyol accumulation) contributes to oxidative stress, which, in turn, could alter intracellular signalling by affecting the regulation of protein kinases that are known to be involved in therapy resistance. Blocking the path of glucose metabolism may help to restore sensitivity to endocrine therapies or it may stop or delay the development resistance endocrine therapies in first place.
While this is a preclinical study, Tekmal believes it could lead to future drug treatments that will make endocrine therapy more effective for longer periods of time.
"This is a very promising study showing that combination treatments seem to work on resistance and re-sensitizing tumors that are resistant to endocrine therapies," he said.

Listen to a recording of the teleconference:










Download* the mp3 of the teleconference (13.2 MB, 58 minutes and 04 seconds)



See Vitamin C




Breast Cancer Res Treat. 2009 Nov 27. [Epub ahead of print]
ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole.

Smollich M, Götte M, Fischgräbe J, Macedo LF, Brodie A, Chen S, Radke I, Kiesel L, Wülfing P.
Department of Obstetrics and Gynecology, University Hospital of Münster, Albert-Schweitzer-Str. 33, 48129, Munster, Germany.
Endothelin-1 (ET-1) and endothelin A receptor (ETAR) contribute to the development and progression of breast carcinomas by modulating cell proliferation, angiogenesis, and anti-apoptosis. We investigated antitumoral effects of the specific ETAR antagonist ZD4054 in breast cancer cells and xenografts, and assessed antitumoral efficacy of the combinations of ZD4054 with aromatase inhibitors and fulvestrant. Gene expression changes were assessed by quantitative real-time PCR. Cell proliferation was measured using alamarBlue((R)); migration and invasion assays were performed using modified Boyden chambers. Evaluating the antitumoral efficacy of ZD4054 in vivo, different breast cancer models were employed using nude mice xenografts. ZD4054 reduced ET-1 and ETAR expression in MCF-7, MDA-MB-231, and MDA-MB-468 breast cancer cells in a concentration-dependent manner. ZD4054 inhibited invasion by up to 37.1% (P = 0.022). Combinations of ZD4054 with either anastrozole or letrozole produced significant reductions in migration of aromatase-overexpressing MCF-7aro cells (P < 0.05). Combination of ZD4054 with fulvestrant reduced MCF-7 cell migration and invasion by 36.0% (P = 0.027) and 56.7% (P < 0.001), respectively, with effects significantly exceeding those seen with either compound alone. Regarding tumor volume reduction in vivo, ZD4054 (10 mg/kg) was equipotent to fulvestrant (200 mg/kg) and exhibited additive effects with anastrozole (0.5 mg/kg). These data are the first indicating that selective ETAR antagonism by ZD4054 displays antitumoral activity on breast cancer cells in vitro and in vivo. Our data strongly support a rationale for the clinical use of ZD4054 in combination with endocrine therapies.

PMID: 19943105 [PubMed - as supplied by publisher]





Cancer Res. 2009 Nov 15;69(22):8670-7. Epub 2009 Oct 27.
Heat shock protein 90 inhibitors: new mode of therapy to overcome endocrine resistance.

Wong C, Chen S.
Graduate School of Biological Sciences and Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Aromatase inhibitors are important drugs to treat estrogen receptor alpha (ERalpha)-positive postmenopausal breast cancer patients. However, development of resistance to aromatase inhibitors has been observed. We examined whether the heat shock protein 90 (HSP90) inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) can inhibit the growth of aromatase inhibitor-resistant breast cancers and the mechanisms by which 17-DMAG affects proliferation. Aromatase inhibitor-responsive MCF-7aro and aromatase inhibitor-resistant LTEDaro breast epithelial cells were used in this study. We observed that 17-DMAG inhibited proliferation in both MCF-7aro and LTEDaro cells in a dose-dependent manner. 17-DMAG induced apoptosis and G(2) cell cycle arrest in both cell lines. Although inhibition of HSP90 decreased the levels of ERalpha, the ERalpha transcriptional activity was not affected when cells were treated with 17-DMAG together with estradiol. Moreover, detailed mechanistic studies suggested that 17-DMAG inhibits cell growth via degradation of HSP90 client proteins AKT and HER2. Collectively, results from this study provide data to support that HSP90 inhibitors may be an effective therapy to treat aromatase inhibitor-resistant breast cancers and that improved efficacy can be achieved by combined use of a HSP90 inhibitor and an AKT inhibitor.

PMID: 19861537 [PubMed - indexed for MEDLINE]





[2028] Prediction of Response to Paclitaxel by ChemoFx assay Correlates with Estrogen Receptor Status and Changes in Apoptosis Pathway in Human Breast Cancers.

Wang D, Rice S, Song N, Gingrich D, Shen K, Hancher L Precision Therapeutics, Pittsburgh, PA

Background: Paclitaxel belongs to the taxane family of therapeutics, which have emerged as critically important drugs for breast cancer treatment. In addition to inhibiting cell growth by interfering with microtubule disassembly, its mechanism of action also includes induction of apoptosis. Recent studies suggest that besides being a key predictor for endocrine therapy response, Estrogen Receptor (ER) status also influences sensitivity of breast cancer to paclitaxel, with ER negative tumors being more responsive to the drug.
Methods: The ChemoFx live cell chemoresponse assay was performed on 25 breast cancer cell lines (10 ER+ and 15 ER-). These cells were treated with a range of 10 doses of paclitaxel for 72 hours before DAPI staining of nuclei and counting. AUC (Area Under Curve) values were calculated and additional statistical analysis was performed on the resulting dose-response curves. Differential gene expression analysis was conducted to compare ER+ (n=82) and ER- (n=51) breast cancer patients using a public Microarray database. In addition, 2 of the 25 breast cancer cell lines, T47D (ER+) and SKBR3 (ER-), were treated with paclitaxel, lysed, and analyzed with Western blotting to detect cleaved caspase-3 and cleaved PARP expression, with beta-actin employed as a normal control.
Results: The ChemoFx assay results revealed that none of the ER+ cells were categorized as R (responsive) to paclitaxel, with seven NR (non-responsive) and one IR (intermediate responsive). On the contrary, of the 15 ER- cell lines, three were categorized as R, only four were categorized as NR, and eight were categorized as IR. Statistical analysis suggested that paclitaxel responsiveness based on ChemoFx assay correlates with ER status (Chi-square test, p<0.05), with ER- breast tumors being more responsive to paclitaxel. Microarray analysis revealed differential expressions of genes implicated in the apoptosis pathway (q< 0.05) in ER+ and ER- breast cancers. Western blot analysis showed that paclitaxel induced cleaved caspase-3 and cleaved PARP expressions, both of which are indicators of activation of apoptosis, in SKBR3 cells (ER-), but not in T47D cells (ER+).
Conclusions: ER status appears to predict in part, the response of breast cancer cells to paclitaxel as determined by the ChemoFx assay. ER-negative breast cancer cells are more likely to be responsive, which is consistent with established clinical findings. Our assay also distinguishes between NR/IR and R to paclitaxel within the ER- population. Similar ChemoFx assays are being performed on primary cultures from ER+ and ER- breast cancer patient specimens. Results from RNA microarray and Western blot analyses indicate that differences in gene expression in the apoptosis pathway, and in activation of apoptosis pathway, namely changes in expressions of cleaved PARP and cleaved caspase-3 in response to paclitaxel, may explain differences in the responsiveness of ER+ and ER- breast cancers to paclitaxel. This also suggests a potential role of cleaved PARP and cleaved caspase-3 as biomarkers in addition to ER for prediction of paclitaxel responsiveness in breast cancer.

Friday, December 11, 2009 7:00 AM


Int J Oncol. 2009 Feb;34(2):313-9.
Resistance to paclitaxel therapy is related with Bcl-2 expression through an estrogen receptor mediated pathway in breast cancer.

Tabuchi Y, Matsuoka J, Gunduz M, Imada T, Ono R, Ito M, Motoki T, Yamatsuji T, Shirakawa Y, Takaoka M, Haisa M, Tanaka N, Kurebayashi J, Jordan VC, Naomoto Y.
Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, and Department of Surgery, Okayama City Hospital, Okayama 700-8558, Japan.
Taxanes are approved for the treatment of breast cancer that has spread to the lymph nodes, following surgery and doxorubicin containing chemotherapy. Taxanes have improved the survival of breast cancer patients, especially in estrogen receptor (ER) negative population in clinical settings. This time we examined the relationship between chemosensitivity to Taxanes and expresson of ERalpha in breast cancer cell lines. In vitro effects of paclitaxel in 4 ER-positive and 3 ER-negative breast cancer cell lines were investigated by MTT assay. We also investigated members of Bcl-2 family by Western blotting and RT-PCR to clarify their role in paclitaxel resistance both in ER-positive and in ER-negative cells. ER-negative cell lines were more sensitive to paclitaxel than ER-positive cells. ER-negative KPL-4 and ZR-75-30 cells, which were sensitive to paclitaxel, became resistant when they were treated with demethylation agent, 5-aza-2'-deoxycytidine. Analysis of proapoptotic (Bax) and antiapoptotic (Bcl-2) molecules suggested that Bcl-2 is likely to have a role in the resistance of ER-positive cells. Bcl-2 expression was increased in a time-dependent manner after treatment of ER-positive cell lines with estrogen (E2). On the other hand, Bcl-2 was not detected in ER-negative cell lines. However, no significant difference was detected for Bax mRNA levels before and after E2 treatment in ER-positive and negative cell lines. Activation of ER gene expression in ER-negative KPL-4 cells by 5-aza-2'-deoxycytidine resulted in up-regulation of Bcl-2 mRNA. To support our data, we examined paclitaxel sensitivity in ER-negative MDA-MB-231 and ER stable transfectant cells S30 and JM6. This experiment also showed ER-negative cells were sensitive to paclitaxel but ER-positive cells were resistant to it. These results suggest that ER influenced chemosensitivity to paclitaxel through regulation of Bcl-2 family and regulation of the pathway may be crucial to increase the efficacy of taxanes in ER-positive breast cancer.

PMID: 19148464 [PubMed - indexed for MEDLINE]




Estrogen Receptor Status and Response to Chemotherapy in Advanced Breast Cancer
[older regimens using Cyclophosphamide]

DAVID T. KIANG, MD, PHD, DANIEL H. FRENNING, MD, JULIETTE GAY, RN, ANNE I . GOLDMAN, PHD, AND
B. J. KENNEDY, MD
Tumor estrogen receptor status in women with advanced breast cancer was correlated with clinical response to cytotoxic chemotherapy in a retrospective study. Following an extramural review of the clinical data of 40 patients, 26 responded to chemotherapy (65%). The response rate in 19 receptor-rich tumors was 89% and in 21 receptor-poor tumors, 43% (P < 0.01). The lowest response rate (14%) was observed in seven postmenopausal patients with receptor-poor tumors. Clinical characteristics of patients and variants in chemotherapy programs failed to explain the favorable response of receptor-rich tumors to cytotoxic chemotherapy.
Cancer 46:2814-2817, 1980.





Steroids. 2009 Aug;74(8):635-41. Epub 2009 Mar 4.
Estrogen receptor beta in breast cancer--diagnostic and therapeutic implications.

Hartman J, Ström A, Gustafsson JA.
Department of Biosciences and Nutrition, Novum, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
More than 10 years have passed since the discovery of the second estrogen receptor, estrogen receptor beta (ERbeta). It is now evident that ERalpha is not the only ER in breast cancer cells; in fact, ERbeta is expressed in the majority of breast cancers although at lower levels than in the normal breast. In addition, ERbeta is expressed in breast cancer infiltrating lymphocytes, fibroblasts and endothelial cells, all known to influence tumor growth. By overexpressing or knocking-out ERbeta in breast cancer cell lines, several researchers have investigated its function with respect to proliferation and tumor growth. It appears that ERbeta is anti-proliferative, in many ways antagonising the function of ERalpha. Furthermore, phytoestrogens have a binding-preference for ERbeta and several epidemiological studies indicate a breast cancer preventing effect of this class of compounds. Tamoxifen is one of the standard, adjuvant treatments for ERalpha positive breast cancer, classically thought to mediate its effect through ERalpha. However, in several recent studies, ERbeta has been described as a potential marker for tamoxifen response. In summary, experimental, epidemiological as well as diagnostic studies point towards ERbeta as an important factor in breast cancer, opening up the possibility for novel ERbeta-selective therapies in the treatment of breast cancer.

PMID: 19463683 [PubMed - indexed for MEDLINE]




Steroids. 2008 Oct;73(11):1039-51. Epub 2008 Apr 20.
ERbeta in breast cancer--onlooker, passive player, or active protector?

Fox EM, Davis RJ, Shupnik MA.
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22903, United States.
The role of estrogen exposure in breast cancer risk is well-documented, and both estrogen synthesis and actions through the estrogen receptor (ER) have been targeted by therapies to control hormone-dependent breast cancer. The discovery of a second ER form and its therapeutic implications sparked great interest. Both the original ERalpha and the more recently identified ERbeta subtypes bind and respond similarly to many physiological and pharmacological ligands. However, differences in phytoestrogen binding have been noted, and subtype-specific ligands have been developed. Cell-based assays show that ERbeta and its variants are generally less active on gene transcription than ERalpha, and may influence ERalpha activity; however, both gene- and cell-specific responses occur, and nongenomic activities are less well explored. Specific ligands, and methods to disrupt or eliminate receptor subtype expression in animal and cell models, demonstrate that the ERs have both overlapping and distinct biological functions. Overall, in cell-based studies, ERalpha appears to play a predominant role in cell proliferation, and ERbeta is suggested to be antiproliferative. The potential for distinct populations of breast tumors to be identified based on ER subtype expression, and to exhibit distinct clinical behaviors, is of greatest interest. Several studies suggest that the majority of ER-positive tumors contain both subtypes, but that some tumors contain only ERbeta and may have distinct clinical behaviors and responses. Expression of ERbeta together with ERalpha favors positive responses to endocrine therapy in most studies, and additional studies to determine if the addition of ERbeta to ERalpha as a tumor marker is of clinical benefit are warranted. In contrast, the positive association between ERbeta and HER2 expression in high-grade ERalpha-negative breast cancer does not favor positive responses to endocrine therapy. Expression of ERbeta in specific clinical subpopulations, and the potential for therapies targeting ERbeta specifically, is discussed.

PMID: 18501937 [PubMed - indexed for MEDLINE]




APMIS. 2009 Sep;117(9):644-50.
Estrogen receptor beta--an independent prognostic marker in estrogen receptor alpha and progesterone receptor-positive breast cancer?

Maehle BO, Collett K, Tretli S, Akslen LA, Grotmol T.
Section for Pathology, The Gade Institute, University of Bergen, Haukeland University Hospital, Bergen, Norway. bjorn.mahle@gades.uib.no
Both subtypes of estrogen receptor (ER), ERalpha and ERbeta, are normally present in the mammary gland. The role of ERalpha as a prognostic marker in breast cancer is well established due to the beneficial effect of providing tamoxifen as adjuvant therapy. The role of ERbeta, however, is less clear. To gain insight into the importance of ERbeta in breast cancer, 145 primary breast cancers were examined by immunohistochemistry for ERbeta, and the expression level was compared with ERalpha and progesterone receptor (PR) status. Especially, we wanted to examine the significance of ERbeta in the contrasting ERalpha+/PR+ and ERalpha-/PR- subgroups. In the ERalpha+/PR+ subgroup (dual positive), the survival difference between patients with low, medium and high ER beta level was statistically significant (p = 0.004), with more than 70% of patients with medium and high ERbeta levels surviving 100 months, compared with less than 30% in the group with low ERbeta level. Further, for ERalpha+/PR+ patients there was a reduced risk of fatal outcome by multivariate analysis with increasing ERbeta levels (p(trend) < 0.01 [univariate analysis]; p(trend) = 0.05 [multivariate analysis]). The risk was 31% and 27% for medium and high ERbeta levels, respectively, compared with low ERbeta level, adjusting for standard prognostic factors such as tumor diameter, nuclear tumor grade (quantified by mean nuclear area), lymph node status, and patient age at operation. For patients with ERalpha-/PR- tumors (dual negative), however, there was no association between ERbeta levels and patient outcome. Our findings indicate that ERbeta expression provides independent prognostic information for breast cancers with ERalpha/PR-positive status, a feature typical among screen-detected breast cancers. The role of ERbeta needs to be further evaluated especially in this group of breast cancers.

PMID: 19703124 [PubMed - indexed for MEDLINE]




Use of Metformin(IGF-), Tykerb(EGF) to reverse resistance?:


J Steroid Biochem Mol Biol. 2009 Oct 6. [Epub ahead of print]
Estrogen utilization of IGF-1-R and EGF-R to signal in breast cancer cells.

Song RX, Chen Y, Zhang Z, Bao Y, Yue W, Wang JP, Fan P, Santen RJ.
Department of Internal Medicine, University of Virginia School of Medicine, 450 Ray Hunt Dr., Charlottesville, VA 22903, USA.
As breast cancer cells develop secondary resistance to estrogen deprivation therapy, they increase their utilization of non-genomic signaling pathways. Our prior work demonstrated that estradiol causes an association of ERalpha with Shc, Src and the IGF-1-R. In cells developing resistance to estrogen deprivation (surrogate for aromatase inhibition) and to the anti-estrogens tamoxifen, 4-OH-tamoxifen, and fulvestrant, an increased association of ERalpha with c-Src and the EGF-R occurs. At the same time, there is a translocation of ERalpha out of the nucleus and into the cytoplasm and cell membrane. Blockade of c-Src with the Src kinase inhibitor, PP-2 causes relocation of ERalpha into the nucleus. While these changes are not identical in response to each anti-estrogen, ERalpha binding to the EGF-R is increased in response to 4-OH-tamoxifen when compared with tamoxifen. The changes in EGF-R interactions with ERalpha impart an enhanced sensitivity of tamoxifen-resistant cells to the inhibitory properties of the specific EGF-R tyrosine kinase inhibitor, AG 1478. However, with long term exposure of tamoxifen-resistant cells to AG 1478, the cells begin to re-grow but can now be inhibited by the IGF-R tyrosine kinase inhibitor, AG 1024. These data suggest that the IGF-R system becomes the predominant signaling mechanism as an adaptive response to the EGF-R inhibitor. Taken together, this information suggests that both the EGF-R and IGF-R pathways can mediate ERalpha signaling. To further examine the effects of fulvestrant on ERalpha function, we examined the acute effects of fulvestrant, on non-genomic functionality. Fulvestrant enhanced ERalpha association with the membrane IGF-1-receptor (IGF-1-R). Using siRNA or expression vectors to knock-down or knock-in selective proteins, we further demonstrated that the ERalpha/IGF-1-R association is Src-dependent. Fulvestrant rapidly induced IGF-1-R and MAPK phosphorylation. The Src inhibitor PP2 and IGF-1-R inhibitor AG1024 greatly blocked fulvestrant-induced ERalpha/IGF-1-R interaction leading to a further depletion of total cellular ERalpha induced by fulvestrant and further enhanced fulvestrant-induced cell growth arrest. More dramatic was the translocation of ERalpha to the plasma membrane in combination with the IGF-1-R as shown by confocal microscopy. Taken in aggregate, these studies suggest that secondary resistance to hormonal therapy results in usage of both IGF-R and EGF-R for non-genomic signaling.

PMID: 19815064 [PubMed - as supplied by publisher]




Breast Cancer Res. 2009 Dec 7;11(6):112. [Epub ahead of print]
CDK inhibitors as potential breast cancer therapeutics: new evidence for enhanced efficacy in ER+ disease.

Sutherland RL, Musgrove EA.
Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia. r.sutherland@garvan.org.au.
ABSTRACT: Loss of cell cycle control is a hallmark of cancer, and aberrations in the cyclin-CDK-RB (cyclin-dependent kinase-retinoblastoma protein) pathway are common in breast cancer. Consequently, inhibition of this pathway is an attractive therapeutic strategy, but results from clinical trials of CDK inhibitors in breast cancer have been disappointing. A recent study now shows that in cell culture a selective CDK4/6 inhibitor is preferentially effective in estrogen receptor-positive (ER+) disease and apparently acts synergistically with tamoxifen or trastuzumab. These exciting new preclinical data set the scene for a more targeted approach to further clinical evaluation wherein this class of drugs is targeted to subgroups of ER+ patients, including those with resistance to endocrine therapy, alone or in combination with current standard therapies.

PMID: 20067604 [PubMed - as supplied by publisher]


Am J Health Syst Pharm. 2009 Dec 1;66(23 Suppl 6):S9-S14.
Emerging treatment combinations: integrating therapy into clinical practice.

Wong ST.
The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903-2681, USA. wongse@umdnj.edu
PURPOSE: To review data supporting the effectiveness of emerging treatment options for metastatic breast cancer. SUMMARY: Recent research has focused on several signal-transduction pathways important in the pathogenesis of breast cancer. Mammalian target of rapamycin (mTOR) is a serine-threonine protein kinase that is involved in cell growth and survival. Everolimus, an orally active inhibitor of mTOR, has demonstrated promising efficacy results and a favorable safety profile in initial studies. Epidermal growth factor receptor (EGFR), a cell-surface molecule that has been implicated in the pathogenesis of breast cancer, may also be important in the emergence of resistance to endocrine therapy. Initial clinical studies have suggested that EGFR inhibitors such as gefitinib may delay the development of resistance to endocrine therapy in patients with breast cancer when given concurrently with tamoxifen or an aromatase inhibitor. Finally, considerable recent research has examined the role of epigenetic gene silencing, in which acetylation or deacetylation of DNA modifies the expression of tumor-suppressing genes. The enzyme histone deacetylase (HDAC) suppresses gene transcription by modifying chromatin into a more compact form. HDAC inhibitors have emerged as a potential new treatment option for several cancer types, including breast cancer. The HDAC inhibitor vorinostat has recently been examined in combination with other treatments, including cytotoxic agents and bevacizumab, for the treatment of breast cancer. In one small Phase I and II study, first-line treatment with the combination of vorinostat, paclitaxel, and bevacizumab produced objective responses (partial or complete) in more than 50% of patients with recurrent or metastatic breast cancer. CONCLUSIONS: Although the results of the described studies are promising, randomized controlled clinical trials are needed to better understand the efficacy and safety of emerging treatment options for patients with metastatic breast cancer.

PMID: 19923318 [PubMed - in process]





Int J Cancer. 2009 Nov 10. [Epub ahead of print]
High CCND1 amplification identifies a group of poor prognosis women with estrogen receptor positive breast cancer.

Roy PG, Pratt N, Purdie CA, Baker L, Ashfield A, Quinlan P, Thompson AM.
Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.
CCND1 encodes for the cyclin D1 protein involved in G1/S cell cycle transition. In breast cancer the mechanism of CCND1 amplification, relationship between cyclin D1 protein expression and the key clinical markers estrogen receptor (ER) and HER2 requires elucidation. Tissue microarrays of primary invasive breast cancer from 93 women were evaluated for CCND1 amplification by fluorescent in-situ hybridization and cyclin D1 protein overexpression by immunohistochemistry. CCND1 amplification was identified in 27/93 (30%) cancers and 59/93 (63%) cancers had overexpression of cyclin D1. CCND1 amplification was significantly associated with cyclin D1 protein overexpression (p < 0.001; Fisher's exact test) and both CCND1 amplification and cyclin D1 protein expression with oestrogen receptor (ER) expression (p = 0.003 and p < 0.001; Fishers exact test). Neither CCND1 amplification nor cyclinD1 expression was associated with tumor size, pathological node status or HER2 amplification, but high CCND1 amplification (Copy Number Gain (CNG) >/= 8) was associated with high tumor grade (p = 0.005; chi square 7.915, 2 df) and worse prognosis by Nottingham Prognostic Index (p = 0.001; 2 sample t-test). High CCND1 amplification (CNG >/= 8) may identify a subset of patients with poor prognosis ER-positive breast cancers who should be considered for additional therapy.

PMID: 19904758 [PubMed - as supplied by publisher]



Am J Clin Oncol. 2010 Feb 5. [Epub ahead of print]
Immunological Therapies Can Relieve Aromatase Inhibitor-Related Joint Symptoms in Breast Cancer Survivors.

Zhang Q, Tang D, Zhao H.
From the *Department of Medical Oncology, Tumor Hospital of Harbin Medical University, Harbin, China; and daggerHeiLongJiang Medical Molecular Biology Key Lab, Harbin Medical University, Harbin, China.
OBJECTIVES:: Aromatase inhibitors can cause joint symptoms. The purpose of this pilot study was to evaluate the feasibility of immunologic therapies for this kind of joint symptoms. METHODS:: A total of 16 postmenopausal women with stage I-III breast cancer with joint symptoms related to Aromatase inhibitors were enrolled. They received immunologic therapies of thymosin alpha1 1.6 mg, twice a week for 4 weeks. Outcome measures included the Brief Pain Inventory-Short Form, Western Ontario and McMaster Universities Osteoarthritis index, and the Functional Assessment of Cancer Therapy-General quality of life measure. Interferon-gamma and interleukin-4 were determined to evaluate immunomodulatory activity. Paired Samples Test and linear regression analysis were used to statistics the outcome measures. RESULTS:: From baseline to the end of treatment, patients reported improvement in the mean Brief Pain Inventory-Short Form worst pain scores (5.7-3.4, P < 0.001), pain severity (3.9-2.9, P = 0.01), and pain-related functional interference (4.2-1.8, P < 0.001), as well as the Western Ontario and McMaster Universities Osteoarthritis function subscale and Functional Assessment of Cancer Therapy-General physical well-being (P < 0.001 and P < 0.001, respectively). No adverse events were reported. The mean serum concentrations for secretion of interferon-gamma were significantly lower (P < 0.001); serum concentrations of interleukin 4 were higher (P = 0.02). CONCLUSION:: Immunologic therapies could play a role in reducing Aromatase inhibitor- related joint symptoms in breast cancer survivors and affecting the immune system in powerful ways. The improvements of immune system were associated with aromatase inhibitor-related joint symptoms.

PMID: 20124972 [PubMed - as supplied by publisher]


Clin Cancer Res. 2010 May 11. [Epub ahead of print]
Tumor Metabolism and Blood Flow as Assessed by Positron Emission Tomography Varies by Tumor Subtype in Locally Advanced Breast Cancer.

Specht JM, Kurland BF, Montgomery SK, Dunnwald LK, Doot RK, Gralow JR, Ellis GK, Linden HM, Livingston RB, Allison KH, Schubert EK, Mankoff DA.
Authors' Affiliations: Medical Oncology and Nuclear Medicine, Departments of Medicine and Pathology, University of Washington, Seattle, Washington; Clinical Statistics, Fred Hutchinson Cancer Research Center, Seattle, Washington; and Medicine, Arizona Cancer Center, Tucson, Arizona.
Abstract

PURPOSE: Dynamic positron emission tomography (PET) imaging can identify patterns of breast cancer metabolism and perfusion in patients receiving neoadjuvant chemotherapy (NC) that are predictive of response. This analysis examines tumor metabolism and perfusion by tumor subtype. EXPERIMENTAL DESIGN: Tumor subtype was defined by immunohistochemistry in 71 patients with locally advanced breast cancer undergoing NC. Subtype was defined as luminal [estrogen receptor (ER)/progesterone receptor (PR) positive], triple negative [TN; ER/PR negative, human epidermal growth factor receptor 2 (HER2) negative], and HER2 (ER/PR negative, HER2 overexpressing). Metabolic rate (MRFDG) and blood flow (BF) were calculated from PET imaging before NC. Pathologic complete response (pCR) to NC was classified as pCR versus other. RESULTS: Twenty-five (35%) of 71 patients had TN tumors; 6 (8%) were HER2 and 40 (56%) were luminal. MRFDG for TN tumors was on average 67% greater than for luminal tumors (95% confidence interval, 9-156%) and average MRFDG/BF ratio was 53% greater in TN compared with luminal tumors (95% confidence interval, 9-114%; P < 0.05 for both). Average BF levels did not differ by subtype (P = 0.73). Most luminal tumors showed relatively low MRFDG and BF (and did not achieve pCR); high MRFDG was generally matched with high BF in luminal tumors and predicted pCR. This was not true in TN tumors. CONCLUSION: The relationship between breast tumor metabolism and perfusion differed by subtype. The high MRFDG/BF ratio that predicts poor response to NC was more common in TN tumors. Metabolism and perfusion measures may identify subsets of tumors susceptible and resistant to NC and may help direct targeted therapy. Clin Cancer Res; 16(10); 2803-10. (c)2010 AACR.

PMID: 20460489 [PubMed - as supplied by publisher]

My interpretation:
Higher uptake meant more probably triple negative and less response to chemo. Luminal (ER+/PR+) usually 67% lower uptake but..if high uptake occurred in a "luminal" tumor, likely to respond well to chemo.
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Re: ER+ issues

Adv Exp Med Biol. 2008;630:19-34.
Adaptation to estradiol deprivation causes up-regulation of growth factor pathways and hypersensitivity to estradiol in breast cancer cells.

Santen RJ, Song RX, Masamura S, Yue W, Fan P, Sogon T, Hayashi S, Nakachi K, Eguchi H.
Division of Endocrinology and Metabolism, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA. rjs5y@virginia.edu


Abstract


Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby Long Term Estradiol Deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response including up-regulation of ERalpha and the MAP kinase, PI-3-kinase and mTOR growth factor pathways. ERalpha is 4-10 fold up-regulated as a result of demethylation of its C promoter, This nuclear receptor then co-opts a classical growth factor pathway using SHC, Grb-2 and Sos. This induces rapid nongenomic effects which are enhanced in LTED cells. The molecules involved in the nongenomic signaling process have been identified. Estradiol binds to cell membrane-associated ERalpha which physically associates with the adaptor protein SHC and induces its phosphorylation. In turn, SHC binds Grb-2 and Sos which results in the rapid activation of MAP kinase. These nongenomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI-3-kinase and mTOR pathways through estradiol-induced binding of ERalpha to the IGF-1 and EGF receptors. A major question is how ERalpha locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-1 receptor serves as an anchor for ERalpha in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, SHC and the IGF-1 receptor itself. SHC, after binding to ERalpha, serves as the "glue" which tethers ERalpha to SHC binding sites on the activated IFG-1 receptors. Use of siRNA methodology to knock down SHC allows the conclusion that SHC is needed for ERalpha to localize in the plasma membrane. In order to abrogate growth factor induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1 and reduces the activation of MAP kinase. We have shown that this drug is a potent inhibitor of mTOR and this provides the major means for inhibition of cell proliferation. The concept of "adaptive hypersensitivity" and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.

PMID: 18637482 [PubMed - indexed for MEDLINE]PMCID: PMC2641021Free PMC Article



Breast Cancer Res. 2008;10(6):R103. Epub 2008 Dec 4.
Anti-oestrogens but not oestrogen deprivation promote cellular invasion in intercellular adhesion-deficient breast cancer cells.

Borley AC, Hiscox S, Gee J, Smith C, Shaw V, Barrett-Lee P, Nicholson RI.
Velindre Cancer Centre, Velindre Road, Cardiff, CF14 2TL, UK.


FREE TEXT

Abstract

INTRODUCTION: Anti-oestrogens have been the mainstay of therapy in patients with oestrogen-receptor (ER) positive breast cancer and have provided significant improvements in survival. However, their benefits are limited by tumour recurrence in a significant proportion of initially drug-responsive breast cancer patients because of acquired anti-oestrogen resistance. Relapse on such therapies clinically presents as local and/or regional recurrences, frequently with distant metastases, and the prognosis for these patients is poor. The selective ER modulator, tamoxifen, classically exerts gene inhibitory effects during the drug-responsive phase in ER-positive breast cancer cells. Paradoxically, this drug is also able to induce the expression of genes, which in the appropriate cell context may contribute to an adverse cell phenotype. Here we have investigated the effects of tamoxifen and fulvestrant treatment on invasive signalling and compared this with the direct effects of oestrogen withdrawal to mimic the action of aromatase inhibitors. METHODS: The effect of oestrogen and 4-hydroxy-tamoxifen on the invasive capacity of endocrine-sensitive MCF-7 cells, in the presence or absence of functional E-cadherin, was determined by Matrigel invasion assays. Studies also monitored the impact of oestrogen withdrawal or treatment with fulvestrant on cell invasion. Western blotting using phospho-specific antibodies was performed to ascertain changes in invasive signalling in response to the two anti-oestrogens versus both oestradiol treatment and withdrawal. RESULTS: To the best of our knowledge, we report for the first time that tamoxifen can promote an invasive phenotype in ER-positive breast cancer cells under conditions of poor cell-cell contact and suggest a role for Src kinase and associated pro-invasive genes in this process. Our studies revealed that although this adverse effect is also apparent for further classes of anti-oestrogens, exemplified by the steroidal agent fulvestrant, it is absent during oestrogen withdrawal. CONCLUSIONS: These data highlight a previously unreported effect of tamoxifen (and potentially further anti-oestrogens), that such agents appear able to induce breast cancer cell invasion in a specific context (absence of good cell-cell contacts), where these findings may have major clinical implications for those patients with tumours that have inherently poor intercellular adhesion. In such patients oestrogen deprivation with aromatase inhibitors may be more appropriate.

PMID: 19055788 [PubMed - indexed for MEDLINE]PMCID: PMC2656899Free PMC Article



Eur J Cancer. 2010 May 13. [Epub ahead of print]
Combining Src inhibitors and aromatase inhibitors: A novel strategy for overcoming endocrine resistance and bone loss.

Hiscox S, Barrett-Lee P, Borley AC, Nicholson RI.
Welsh School of Pharmacy, Cardiff, UK.
Abstract

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes. Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20471823 [PubMed - as supplied by publisher]



Coffee (reg& decaf) estrogenic:

http://her2support.org/vbulletin/showthread.php?t=41871&highlight=coffee+es trogen

J Nutr. 2009 Oct;139(10):1833-8. Epub 2009 Aug 26.
Trigonelline is a novel phytoestrogen in coffee beans.

Allred KF, Yackley KM, Vanamala J, Allred CD.
Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA.
Drinking coffee has been associated with the development of several endocrine-related cancers. The interpretation of these data has often been limited to the role that caffeine plays. Trigonelline (Trig), a niacin-related compound, is a natural constituent of coffee accounting for approximately 1% dry matter in roasted beans. Studies exploring the effects of this bioactive compound on mammalian cells are limited. The initial purpose of our studies was to determine whether Trig alters the actions of estradiol (E(2)), using proliferation of estrogen-dependent human breast cancer (MCF-7) cells as a model system. When cells were cotreated with suboptimal doses of E(2) (10 pmol/L) and Trig (100 pmol/L), an additive enhancement of MCF-7 growth was observed. In the absence of E(2), Trig stimulated MCF-7 cell proliferation in a dose-responsive manner and significantly enhanced cell growth at concentrations as low as 100 pmol/L. Cotreatment of MCF-7 cells with Trig and ICI 182,780, an estrogen receptor (ER) antagonist, inhibited Trig-induced cell proliferation. Trig treatment also induced activation of estrogen response element reporter assays in MCF-7 cells and increased expression of ER target genes (pS2, progesterone receptor, and cyclin D1) similar to E(2). While our data demonstrate that Trig activates the ER, competitive binding assays showed that Trig does not compete E(2) off of the ER at any concentration. This suggests that Trig is activating the ER through a separate mechanism. Collectively, these data demonstrate that Trig even at low concentrations stimulates MCF-7 cell growth and that this effect is mediated through ER, clearly identifying Trig as a novel phytoestrogen.
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