[Rich66]

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:

• JAMA. 2009 Dec 9;302(22):2483-4.

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.