(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.
3–5 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
Quote:
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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.13–15 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.
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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.
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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.
Quote:
| 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.
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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.