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Study on the effects of Tamox and Exemestane on cognitive function:

[1133] Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with early breast cancer: results from the TEAM trial neuropsychological side study.

Schilder CM, Seynaeve C, Linn SC, Boogerd W, Beex LV, Gundy CM, Huizenga HM, Nortier JW, v/d Velde CJ, van Dam FS, Schagen SB Netherlands Cancer Institute (NKI), Amsterdam, Netherlands; Erasmus Medical Center, Rotterdam; NKI, Amsterdam; Radboud University Medical Center, Nijmegen; University of Amsterdam, Amsterdam; Leiden University Medical Center (LUMC); LUMC, Leiden, Netherlands

Background
Adjuvant hormonal therapies (HT) are frequently used in primary breast cancer (BC), yet few studies have examined their potential impact on cognition. Fundamental and human research indicate that estrogens play an important role in certain cognitive functions; therefore it is plausible that HT can affect cognition in BC patients (pts). Due to different mechanisms of action, distinctive effects between selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) are possible.
Methods
Neuropsychological examinations were used to study cognitive performance before the start of adjuvant HT (T1) and after one year of HT (T2) in postmenopausal BC pts not qualified to receive chemotherapy. Study pts participated in the Dutch part of the international TEAM-trial, a prospective randomized study investigating tamoxifen (SERM) versus exemestane (AI) as adjuvant therapy for hormone-sensitive BC. The study sample consisted of 80 tamoxifen users (mean age 68.7 yrs, range 51-84) and 99 exemestane users (mean age 68.3 yrs, range 50-82). A healthy control group (n=120, mean age 66.2 yrs; range 49-86) was assessed with a similar interval. Differences in performance at T2 on 8 cognitive domains were studied among the three groups by use of ANCOVA twice: (1) adjusting for performance at T1 and (2) with additional adjustment for the covariates anxiety/depression, fatigue and menopausal symptoms at T2.
Results
After one year of therapy, exemestane users did not perform significantly worse than healthy controls on any cognitive domain. Tamoxifen users performed worse than healthy controls on verbal memory (P=.003, Cohens d = .43) and executive functioning (P=.005, Cohens d = .40) and worse than exemestane users on information processing speed (P=.019, Cohens d = .36). Adjustment for covariates did not change these results. For visual memory, working memory, verbal fluency, reaction speed and motor speed no significant differences between groups were found.
Discussion
After one year of therapy, tamoxifen has a negative impact on certain cognitive functions, while exemestane does not negatively affect cognition in this population. Although the burden of these effects on the daily life of pts has yet to be determined, intact cognition is known to be an important precondition for independent living and wellbeing. Currently, the options of HT in BC are increasing and optimization of HT with respect to the choice, sequence and duration of treatments is given high research priority. Our results underscore the need to include cognitive effects of HT in long-term safety studies.

Thursday, December 11, 2008 5:00 PM


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AI's may Prevent recurrences of ER NEGATIVE AS WELL AS ER++

[1134] NCIC CTG MA.17: hormone receptor expression of in-breast recurrences and contralateral primary breast cancers arising on aromatase inhibitors.

Moy B, Tu D, Shepherd LE, Palmer MJ, Ingle JN, Goss PE Massachusetts General Hospital, Boston, MA; National Cancer Institute of Canada Clinical Trials Group, Kingston, ON, Canada; Mayo Clinic, Rochester, MN

Background: The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of ER+ (but not ER-) invasive breast cancers in healthy women at high risk for developing breast cancer. Aromatase inhibitors (AIs) given as adjuvant therapy to treatment-nave or post-tamoxifen patients significantly reduce the risk of in-breast recurrences (IBRs) and contralateral breast cancers (CBCs) and are currently in clinical trials for breast cancer prevention (NCIC CTG MAP.3 and IBIS-II). It is hypothesized that SERMS inhibit promotion of ER+ breast cancer whereas AIs may reduce both ER+ and ER- breast cancer by inhibiting both tumor initiation and promotion. Little is known about the characteristics of IBRs and CBCs that arise on AI therapy. We present the ER/PR expression and clinicopathologic features of IBRs and CBCs that occurred on MA.17.
Methods: We examined ER/PR status of IBRs and CBCs that arose on letrozole vs. placebo among women enrolled in MA.17, a placebo-controlled (PLAC) trial of letrozole (LET) following 5 years of tamoxifen in postmenopausal women with early stage breast cancer.
Results: Seventy-one patients (pts) developed an IBR and 87 developed a CBC on trial. Consistent with results previously reported, fewer IBRs (LET 20 vs PLAC 51) and CBCs (LET 35 vs PLAC 52) were observed in the LET group. ER and PR status is currently available on 35 women with an IBR and 39 with a CBC. The majority of IBRs were ER+ in both the LET and PLAC groups (10/11 [91%] vs 18/24 [75%], respectively; p=NS) but numbers of both ER+ and IBRs were less in LET group, suggesting that letrozole may decrease both ER+ and ER- IBRs. CBCs that arose on PLAC were more likely to be ER+ than on LET (16/22 [73%] vs 6/19 pts [32%], respectively; p=0.01), suggesting that letrozole predominantly prevents ER+ CBCs. Discordance in ER expression between primary breast cancer and IBRs among women randomized to LET vs. PLAC was observed in 1/11 [9%] and 6/24 [26%] women respectively (p=NS) and between primary breast cancer and CBCs in 12/18 pts [67%] vs. 6/21 [29%] women respectively (p=0.01). Other clinicopathologic characteristics such as grade, tumor size, PR, HER-2/neu, and nodal status of IBRs and CBCs will be presented at the meeting.
Conclusion: Extended adjuvant endocrine therapy with letrozole results in fewer IBRs and CBCs compared with placebo as previously reported. Our data suggests that letrozole may decrease both ER+ and ER- IBRs. Letrozole appears to prevent ER+ CBCs but has little or no apparent effect on the development of ER- CBCs. These results need confirmation in the primary prevention trials of AIs.

ER status of IBRs and CBCs

LetrozolePlaceboTotal
ER status of IBRs


Positive10 (91%)18 (75%)28 (80%)
Negative1 (9%)6 (25%)7 (20%)
ER status of CBCs


Positive6 (32%)16 (73%)22 (54%)
Negative13 (68%)6 (27%)19 (46%)






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SWITCHING TO FEMARA HELPS WITH PAIN!

[1142] Effects of switching aromatase inhibitors on arthralgia: the ATOLL study.

Briot K, Bastit L, Rotarsky M, Spaeth D, Tubiana M, Mauresan Kloos I, Bourdeix I, Roux C Paris Descartes University, Cochin Hospital, Paris, France; F. Joliot Center, Rouen, France; Clinique Oncologique, Bayonne, France; Centre dOncologie Gentilly, Nancy, France; Rene Huguenin Institute, St. Cloud, France; Novartis Pharma S.A.S., Rueil-Malmaison Cedex, France

Background: Aromatase inhibitors (AIs) are standard adjuvant therapy in postmenopausal women (PMW) with hormone receptor-positive breast cancer (HR+BC). The estrogen-deficient environment induced by AIs may predispose women to increased bone loss and arthralgia. Switching from one AI to another has been shown to improve arthralgia. However, clinical trial data documenting the course of joint pain symptoms in switching studies has been sparse. The Articular Tolerance of Letrozole (ATOLL) study evaluates the tolerability of letrozole (L) in patients who were switched from anastrozole (A) due to severe joint pain.
Objectives: This study included PMW with HR+BC who experienced severe joint pain with A requiring discontinuation and then switched to L. The aim of the study was to (i) determine the incidence of L discontinuation due to joint pain (ii) identify predictive factors for L tolerance.
Methods: Only PMW with HR+ BCwho experienced severe joint pain on A requiring discontinuation were eligible for this 6-month prospective open-label, multi-centre trial. Treatment with L was initiated following a 1 month washout period. Pain assessment was done by a oncologist just prior to L initiation and after six months of follow up. Outcomes were based on patient reports of joint pain after initiating L. A central review was done by a rheumatologist. Statistical evaluations were determined on a 95% CI, and correlations were performed using a Cox model.
Results: 179 PMW with HR+ breast cancer (mean age 61.3 8.4) were eligible. The mean duration of A treatment prior to discontinuation was 14.6 10.59 months with 126 (73.7%) on A for more than 6 months. At the end of the 6 month follow-up, 128 patients (71.5%) remained on L and continued by choice while 51(28.5%) patients discontinued L due to worsening of joint pain;73.5% patients discontinued due to arthralgia and 21% due to muscle pain . Hands, knees and spine were the most commonly affected joints. There was no association between L discontinuation with age, duration of menopause, socio-demographic status or previous joint disorders including osteoarthritis. The predictor of L discontinuation was significant only for the duration of the previous A treatment (p=0.04).
Conclusion: These data suggest switching from anastrozole to letrozole may help to maintain the benefit of AI therapy in patients who complain with severe joint pain and support the reported findings of Renshaw et al that more than 50% of women obtained relief of joint pain by switching from one AI to another. Symptomatic arthralgia due to prolonged use of A reduced the usefulness of switching to L in this patient cohort, therefore, switching from one AI to the other at the onset of symptoms may help to maintain the benefit of AI therapy in patients who complain of severe joint pain.



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Chinese Medicine Offers Real Hope for Triple Negs!!!!!
[2116] The mechanism of Astragalus membranaceus effects on the proliferation of human basal-like breast cancer cell line MDA-MB-468 from p53/MDM2 pathway.

Ye MN, Chen HF, Deng Y Longhua Hospital, Shanghai, Shanghai, China

Background: Based on the expression of ER,PR and Her2, breast cancer is classified into several subtypes. Thereinto, basal-like type (triple-negative phenotype) is associated with poor prognosis. Patients with this type are unlikely to benefit from currently available targeted therapy. And some researches revealed traditional Chinese medicine could play an important role in breast cancer treatment. p53 mutations can be found in most of basal-like breast cancer patients and this types cell lines. In our study, we mainly focused on the mechanism of Astragalus membranaceus effect on the proliferation of MDA-MB-468 cell from p53/MDM2 pathway.
Material and Methods: The MDA-MB-468 cells were intervened by Astragalus membranaceus Injection (AMI) which contains 1g/ml crude drugs. The effect of AMI on the proliferation of the MDA-MB-468 cells was detected by MTT assay and its time-effect relationship was observed by cell counting kit-8 (CCK-8) assay. At two days after AMI intervention, the mRNA expression of some indicators were assessed by Real-time Quantitative PCR, including p53, MDM2, EGFR, PIP, PI3K, Akt1, Akt2 and PTEN. The anti-proliferation effect of AMI on the cells proliferation was detected by MTT assay after PTEN gene was knocked down by the small interfering RNA (SiRNA), and the protein expressions of EGFR, p-Akt, MDM2 and p53 were obtained by in-cell western assay.
Results: According to MTT assay, AMI could obviously inhibit the proliferation of the MDA-MB-468 cells (p<0.05) and the effect was stronger when combined with Tarceva (p<0.01); When the PTEN gene was knocked down, AMI only combined with Tarceva could inhibit the cells proliferation (p<0.005). CCK-8 assay showed that the anti-proliferation effect of AMI was positively correlated with the intervention duration. Real-time Quantitative PCR revealed that AMI could up-regulate the PTEN gene expression (p<0.001) and down-regulate the p53 (p<0.01), MDM2 (p<0.01), Akt2 (p<0.001) and PIP (p<0.001) gene expressions. In-cell western assay indicated that p53 protein was down-regulated at 15min(p<0.05) and 1h(p<0.001), and p-Akt protein expression showed significant down-regulation at 15min(p<0.01), 30min(p<0.001) and 2d(p<0.001) after AMI intervene; when AMI combined with Tarceva, the duration of the down-regulation effect to p53 and p-Akt were all prolonged, and EGFR and MDM2 expressions were down-regulated(p<0.05, p<0.005). After PTEN SiRNA intervene, AMI down-regulate p53 (p<0.001), p-Akt (p<0.005) and EGFR (p<0.05) protein expressions; and its down-regulation effect to p-Akt reduced, but increased to p53, and EGFR.
Discussion: AMI can significantly inhibit the proliferation of MDA-MB-468 cells and present a time-dependent manner. The effect became stronger after combined with Tarceva. The main mechanism of its anti-proliferation effect may be to activate the positive feedback loop of the p53/ MDM2 pathway. It negatively regulates the PI3K by up-regulating the PTEN gene expression to promote the phosphorylation at D3 point of PIP3, so Akts phosphorylation level is down-regulated and the cells proliferation was inhibited.



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MORE HOPE FOR TN!

[2119] Targeting of breast cancer with non-oncology drugs possible novel therapeutic option for triple-negative breast cancer.

Liedtke C, Yan K, Wu Y, Hortobagyi GN, Symmans WF, Valero V, Goette M, Kiesel L, Pusztai L University Muenster, Muenster, Germany; The University of Texas M.D. Anderson Cancer Center, Houston, TX

Introduction: Triple-negative breast cancer (TNBC) is defined by lack of ER, and PR expression and normal HER2 expression. It is characterized by aggressive biological presentation and unfavorable outcome. It is associated with frequent lack of response to current chemotherapy agents. Recently, 392 drugged genes that serve as targets for 1557 both oncologic and non-oncologic drugs were identified from the pharmacologic database DrugBank (Lauss et al. Pharmacogenomics 2007). In this study, we compared expression levels of these known drug targets between TNBC and receptor-positive cancers. Methods: Gene expression profiles were obtained from fine needle biopsies of newly diagnosed early stage breast cancer before any therapy (n=133, MDACC dataset). Differential expression of these genes was validated in a second independent data set (n=286, Rotterdam dataset) and in a panel of cell lines (n=19). In order to assess the functional relevance of known drug targets overexpressed in TNBC we performed in vitro experiments. Cell lines were treated with various concentrations of selected drugs alone or in combination with paclitaxel. Results: We mapped 675 U133A probe sets representing 347 unique drug targets to the Affymetrix U133A Genechip. 44 drug targets were overexpressed in TNBC compared to non-TNBC in the MDACC dataset. Thirty-three of these (75%) were also overexpressed among TNBC compared to non-TNBC in the Rotterdam dataset. Glutathione-S-transferase pi (GSTpi, target of clomipramine) was the most highly and consistently overexpressed target in human TNBC and in estrogen- and HER2-receptor-negative breast cancer cell lines. The GSTpi overexpressing (and triple negative) human mammary cell line HBL-100 showed dose-dependent inhibition of growth after 144 hrs of incubation with clomipramine, whereas growth of the GSTpi-low expressing (non-triple negative) breast cancer cell lines MCF-7 and SKBR3 was not inhibited by this drug. Treatment with clomipramine did not alter sensitivity to paclitaxel in either cell line in vitro. Conclusion: Gene expression analysis indicates that targets for several known drugs are over expressed in TNBC relative to other types of breast cancers. We hypothesize that some of these drugs may influence the behavior of TNBC and may represent future therapeutic options. Further experiments are needed to fully explore the functional implications of these findings; however, our preliminary results suggest that inhibition of GSTpi with clomipramine leads to inhibition of cell growth of TNBC cell lines in vitro.



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COMBO TX VS SINGLE TX ON METS

[2121] Combination or sequential single agent for the treatment of metastatic breast cancer (MBC) patients (pts). Impact of further chemotherapy (CT) in overall survival (OS) in the Alamo registry.

Lluch A, Ruiz A, Martín M, Alba E, Pastor M, de la Haba J, Llombart A, Ramos M, Martínez del Prado P, Escudero MJ H C U Valencia, Valencia, Spain; IVO, Valencia, Spain; H C U San Carlos, Madrid, Spain; C H Virgen de la Victoria, Mlaga, Spain; H U La Fe, Valencia, Spain; C H Reina Sofa, Crdoba, Spain; H U Arnau de Vilanova, Lleida, Spain; C O Galicia, A Corua, Spain; H Basurto, Bilbao, Spain; GEICAM, Madrid, Spain

Introduction: Combinations can improve OS in MBC; however sequential single agent is sometimes preferred. In a recent report, pts receiving paclitaxel monotherapy in first line had a significantly worse OS if they were not receiving post study CT (PSC); no difference was seen in pts receiving paclitaxel+gemcitabine (Llombart, EBCC 2008). In this trial only 58% of pts received PSC.
Purpose: To assess, outside the context of a clinical trial, the amount of MBC pts receiving CT beyond first line, as well as the impact of combination use and further CT lines in their OS.
Methods: Alamo 1-2 is a breast cancer patient registry run by the GEICAM. 15482 pts diagnosed from 1990-1997 in 54 sites were included in the database. 4668 pts were stage IV; 778 (16.7%) metastatic at diagnosis and 3890 (83.3%) have had a recurrence.
Results: 3045 (65%) pts received CT in first line, 83% were combinations (with anthracyclines 42%, CMF 16%, taxane+anthracyclines 9.4% or +other agents 8%) and 16% were monotherapy. Among other variables studied, only previous treatment (in early stage) was influencing the choice of a combination (pts without previous CT received more combinations than pts receiving CMF, than pts receiving anthracyclines). Median survival for pts receiving single agent was significantly shorter compared to pts receiving combination, 16.2 and 21.85 months (m) respectively, HR=1.37 (IC 95%: 1.21-1.55; p<0.0001). Several covariates showed significant prognostic value in survival in the Cox multivariate model: monotherapy treatment in first line, anthracyclines pre-exposure, age > 65, negative hormonal receptor status, hepatic disease, Grade 3 and 3 disease sites. Half of the pts never received further CT after first line treatment. Only age and number of disease sites were influencing this decision in the Cox multivariate model. Median survival was 24.9 m in pts receiving further CT and 14.5 m in the ones not receiving it. In pts not receiving further CT, median OS was significantly shorter if they were treated with single agent in first line in comparison to those receiving previous combination: HR= 1.59 (IC 95%: 1.33-1.89; p< 0,00001). This difference was not significant in pts receiving further CT: HR= 1.15 (IC 95%: 0.97-1.37; p=0.101).
Conclusion: Our data show that only half of the MBC pts receive further CT after first line; they have longer survival. We found significant evidence that further CT is impacting the OS in pts treated with single agent in first line, but not in those receiving previous combination. Those facts should be taken into consideration when selecting single agent or a combination in first line.


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Adding New Viral Therapy- Promising!

[2129] Combination of oncolytic adenoviral therapy with chemotherapy for enhanced breast cancer cell killing.

Stoff-Khalili MA, Nedeljkovic-Kurepa A, Jung JS, Glover BV, Wappenschmidt B, Rhiem K, Bosse K, Mallmann P, Curiel DT, Schmutzler RK, Mathis MJ University of Cologne, Cologne, Germany; LSU, Shreveport, LA; University of Alabama at Birmingham, Birmingham

Oncolytic adenoviruses are emerging agents for treatment of cancer by tumor-restricted virus replication, cell lysis and virus spread. A promising oncolytic adenovirus agent, known as Ad5-24-RGD, harbors a 24-bp deletion in the E1A gene that abrogates the binding of E1A to the retinoblastoma tumor suppressor (Rb) and presents enhanced infectivity of primary cancer cells due to insertion of an Arg-Gly-Asp (RGD) motif into the fiber knob. Thus, Ad5-24-RGD has improved cancer cell infection efficiency due to expanded tropism toward alpha-v integrins. It also replicates selectively in cancer cells with Rb/p16 mutations. As with conventional therapy regimes, oncolytic virotherapy, by itself, has limited success in complete tumor eradication in both preclinical animal models and clinical studies. Combination of anticancer agents with different modes of action remains a mainstay in cancer treatment. We undertook one approach towards this end by combining oncolytic adenoviral therapy with chemotherapy. In this study, we investigated a combination treatment of breast cancer cells with Ad5-4-RGD and Docetaxel, a microtubule-stabilizing taxane that is being used in the clinic for the treatment of breast and prostate cancers and small cell carcinoma of the lung. Our results indicate a synergistic effect between Docetaxel and Ad5-24-RGD in breast cancer cell killing at a lower dose than either agent alone. These results suggest that viral replication was not inhibited by this chemotherapy treatment and that chemotherapy could reduce the amount of viral particles needed to help eradicate the tumor. Administration of lower viral loads would simultaneously improve safety and decrease immunogenicity of the vector. Likewise lower doses of chemotherapy agents would decrease toxicity and side effects. The inclusion of oncolytic adenoviruses into multimodal cancer treatment together with chemotherapy has a potential to become powerful therapeutic regimen.


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MORE HOPE FOR METS!

[2131] A multi-center phase II study of three doses of TAS-108 in postmenopausal women with advanced breast carcinoma following first or second line endocrine therapy.

Buzdar A, Tan-Chiu E, Schwartzberg L, Perez A, Ellis M, Garin A, Ingle J, Carlson R MD Anderson Cancer Center, Houston, TX; Florida Cancer Research Institute, Davie, FL; The West Clinic, Memphis, TN; Memorial Regional Hospital, Hollywood, FL; Washington University, St. Louis, MO; Russian Cancer Research Institute, Moscow, Russian Federation; Mayo Clinic, Rochester, MN; Stanford Cancer Center, Stanford, CA

Introduction: TAS-108 is an oral steroidal anti-estrogen agent that selectively inhibits ER and is mainly metabolized by CYP3A4. The purpose of this study is to investigate the efficacy and safety of TAS-108 administrated orally in three dose levels in patients with locally advanced, locally recurrent inoperable or metastatic breast carcinoma (BC) in four countries (USA, Russia, Mexico and Chile).
Methods: Postmenopausal women with confirmed ER and/or PgR positive BC who had previously responded to one or two standard endocrine therapies, with or without one prior chemotherapy were randomly assigned to three doses of TAS-108, 40 mg, 80 and 120 mg daily. Using a modified Panageas optimal two-stage trinomial design, the enrollment of 60 evaluable patients (first-stage: 19) was required to each individual dose group. Tumor response was assessed every 8 weeks according to RECIST criteria. Adverse events (AEs) were graded by CTC-AE v3.0.
Results: A total of 146 patients with mean age of 63 years old were enrolled with 61 patients in the 40 mg group and 66 in the 80 mg group. The 120 mg group was terminated at the end of stage 1 with 19 patients enrolled due to lack of efficacy. The mean duration of study treatment was 172 days for the 40 mg group and 160 days for the 80 mg group. Partial response (PR) was documented in 6 (10%) patients in the 40 mg group and 4 (6.7%) patients in the 80 mg group. The rate of disease stabilization (CR+PR+SD) reported by the investigators was 43% (95%CI, 31%,56%) in the 40 mg group and 45% (95%CI, 32%,58%) in the 80 mg group. Adjudicated clinical benefit (CR+PR+SD more than 24 wks) was observed in 22% of patients in the 40 mg group and 20% of patients in the 80 mg group. Clinical benefit was achieved in 25% of patients with 1 prior hormonal therapy and 15% of patients with more than one line of prior hormonal therapy. Median time to progression (TTP): 15 weeks for the 40 mg group and 15.9 weeks for the 80 mg group. Median duration of clinical benefit was 32 weeks in the 40 mg group and 64 weeks in the 80 mg group. In the 40/80/120 mg groups, the commonly reported treatment-related AEs included nausea (15%/11%/16%), fatigue (10%/11%/16%), headache (10%/6%/16%), hot flushes (10%/5%/32%), diarrhea (2%/6%/5%), constipation (3%/3%/5%), and arthralgia (2%/5%/11%). No endometrial cancer and treatment-related deaths occurred during the study.
Conclusions: TAS-108 has demonstrated anti-tumor activity in this population and was generally well tolerated. The 40 mg dose was chosen as the recommended dose for future clinical evaluation in patients with advanced breast cancer.



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MORE TO COME LATER......

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Reply with quote  #10 
Gina - wow - tons of info to absorb. 
 I found the results of cognitive functioning interesting, especially since I am Aromasin (but I have taken all 3 plus tamox over the past almost 2 1/2 years, though I have been on Aromasin the longest) - not what I expected.  I wonder if the results would be different with younger women.  I thought of having a neuropsych a few months ago, but without a baseline to compare to, I decided it was a waste of time and money.  So are perceived or real memory problems, attention and focus problems etc a result of chemo, AI's,  stress or depression  all following Dx and Tx of BC?  I so believe that I do not function as well now as before Dx and do not believe it is just because I past the big 50. 
Will be interested to see what future studies find - will there be future studies based on these results??!!!
Hugs, Karen 
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Gina, you are full of good news today! Very encouraging what I was able to pick up. I'll have to come back to absorb more, but the drop in cognitive function certainly rings true to me. Took me months to clear out the fog from about 12 days on Tamox. So relieved to hear it shouldn't be a S/E of the AI's. Seriously, you made my day!
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Hi guys!
When all the reports are in, we will break them down and discuss them... weed out the Doctor speak!




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LOW ER? No Problem!
[1065] Effects of letrozole and anastrozole on low ER expressing invasive breast carcinomas: results from a randomised trial.

Faratian D, Renshaw L, Caldwell H, Williams L, Murray J, Young O, Evans DB, Thomas JS, Harrison DJ, Dixon JM University of Edinburgh, Edinburgh, United Kingdom; Novartis Institutes of BioMedical Research Basel, Basel, Switzerland

Introduction:
Changes in proliferation as measured by Ki67 occur within 14 days of starting treatment with an aromatase inhibitor and have been shown to be predictors of long term outcome. The biological effect of different aromatase inhibitors on low ER expressing cancers has not been studied. This study compared changes in proliferation in breast cancers expressing low levels of ER (Allred score 2-5) following 14 days of treatment with anastrozole or letrozole.
Materials and methods:
Thirty six postmenopausal women with invasive breast cancer, classified as estrogen receptor (ER) poor by an Allred score of 2-5 on initial core biopsy, were enrolled into a randomised pre-operative trial of 14 days treatment with either 2.5 mg of letrozole or 1 mg of anastrozole. Paired biopsy tissue was available for all patients: [15 who received anastrozole and 21 letrozole] with sufficient invasive cancer present for analysis. Assessment included ER (Allred score) and proliferation (% tumor cells Ki67 positive) by immunohistochemistry. Results are presented as means (SEM) and medians (range). Due to the non-normality of the data, pre- and post-treatment Ki67 values were transformed on the log scale. Change between pre- and post- treatment scores was calculated as the difference in the logged scores; analysis is by t-test and Fishers Exact Test. All tests are two-sided. Results were back-transformed in order to preserve the original scale.
Results:
Proliferation measured by Ki67:
Anastrozole reduced tumour cell proliferation from baseline in 10/15 cancers from a mean of 31.0% (7.1) to 20.8% (6.1). The median and mean reductions in Ki67 were 37% (range -94.0% to 92.6%) and 38% (13.9) from baseline. This equates to an average fall of 2.6 times from baseline, p=0.006, by analysis of the transformed data.
Letrozole reduced proliferation from baseline in 17/21 cancers from a mean of 39.0% (7.3) to 25.3% (6.4). The median and mean reductions were 67% (range -115.6% to 99.6%) and 46% (10.6) from baseline. This equates to an average fall of 3.13 times from baseline, p=0.0002, by analysis of the transformed data.
There was no evidence of a significant difference between drugs in reduction of proliferation, the number of cases showing a fall in proliferation, or the absolute Ki67 index at 14 days. Only 3/15 (anastrozole) and 2/21 (letrozole) tumours had post-treatment absolute Ki67 indices of 1%. There were no significant differences in changes in proliferation between tumours with ER score 2-3 vs score 4-5.
Conclusions:
1. Both anastrozole and letrozole significantly reduced proliferation in invasive cancers with low ER expression.
2. There were no evident significant differences between drugs.
3. These data suggest that aromatase inhibitors are of value even in low-ER expressing cancers, either on their own or perhaps as part of combined therapy.
4. Analysis of more patients and of biological response according to molecular phenotype is underway.



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Reply with quote  #14 
Thank you Gina!!!!


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Here is a good link from Medscape.com

http://www.medscape.com/viewprogram/17896?src=mp&spon=7&uac=30793PT

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Reply with quote  #16 
Intersting link, thank you!

What do you all think of the estrogen in moisturizers??? Is that weird or what?
What kind can we use? What would be safe? Vaseline maybe? I stopped using body lotions completely after dx but my face needs something. I can't open my eyes if I don't put some creme around them......

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