[Rich66]

Maybe it's still is an issue in metastatic BC:

From the above study:

The objective of the present analysis was to evaluate the frequency of CNS relapse in patients treated with or without adjuvant taxanes. This question was studied because taxane treatment in advanced breast cancer was associated with high
CNS relapse rates in some studies (up to 30%) [5, 6].

In recent years, high rates of CNS relapse have been observed in smaller studies of patients treated with taxane-based (14% and 30%) [5,6] or with trastuzumab-based (34% and 39%) [10,11,12] therapy for metastatic breast cancer. The reason for these higher rates are unknown, although efficacy in the systemic ‘compartment’ in conjunction with restricted efficacy of these treatments in the CNS ‘compartment’ [11], heterogeneity in tumour cell biology [13] and/or drug interactions with the blood brain barrier can be considered.

Advanced Breast Cancer: Treatment
with Docetaxel/Epirubicin:

An interesting observation regarding a higher incidence of central nervous system (CNS) involvement in patients treated with docetaxel/epirubicin was reported by an Italian group, based on a pooled analysis of their phase I and II studies (Pagani et al., 1999, 2000). A total of 92 patients were included in these two studies and the authors reported that 28 (30%) of the 92 patients treated with this combination
developed CNS metastases; 25 patients developed cerebral metastasis, two leptomeningeal, and one both (Crivellari et al., 2001). Median time for the development of CNS metastases from the start of chemotherapy was 15 months (range 5–42), when the six patients presenting CNS progression within 3 months from start of treatment were excluded. It is noteworthy that 11 patients (39%) had disease progression only in the CNS. Although, this observation could be easily explained by the sanctuary site ‘hypothesis’, as a consequence of an intact blood-brain barrier, this is not proven and the exact explanation remains to be elucidated. The authors conclude that as anthracycline and taxane containing regimens are increasingly used both in the metastatic and in the adjuvant setting, a careful monitoring of any neurological symptoms should be advisable.

5. Freilich RJ, Seidman AD, DeAngelis LM. Central nervous system progression of metastatic breast cancer in patients treated with paclitaxel. Cancer 1995; 76:232–236.

6. Crivellari D, Pagani O, Veronesi A et al. High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel. Ann Oncol. 2001; 12: 353–356.

7. Pestalozzi BC, Zahrieh D, Price KN et al. for the International Breast Cancer Study Group (IBCSG). Identifying breast cancer patients at risk for central nervous system (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol. 2006; 17: 935–944.

In advanced breast cancer, a high incidence of CNS metastases was found in women treated with taxanes, 14% and 30%, respectively [21, 22]

. Similarly, a high incidence (34%) of CNS metastases was found among patients treated with trastuzumab for stage IV breast cancer [23, 24]. Because trastuzumab does not cross the blood-brain barrier [25], this higher incidence may reflect prolongation of disease control in the systemic compartment but not in the CNS. In addition, HER2-positive tumors are known to behave more aggressively, and it may be their biological behavior that results in an increased rate of CNS metastasis...Prophylactic cranial irradiation is not justified for any cohort of breast cancer patients at this time.

8. Gonzales-Angulo AM, Cristofanilli M, Strom EA et al. Central nervous system metastases in patients with high-risk breast carcinoma after multimodality treatment. Cancer 2004; 101: 1760–1766.
Central nervous system metastases in women after multimodality therapy for high risk breast cancer.

Carey LA, Ewend MG, Metzger R, Sawyer L, Dees EC, Sartor CI, Moore DT, Graham ML.
Division of Hematology/Oncology, Department of Medicine, University of North Carolina, 3009 Old Clinic Building, Chapel Hill, NC, 27599-7305, USA. lisa_carey@med.unc.edu
Comment in:

• Breast Cancer Res Treat. 2005 Feb;89(3):317.

BACKGROUND: Central nervous system (CNS) relapse is increasing in breast cancer. This increase may reflect altered failure patterns from adjuvant therapy, more effective systemic therapy with improved control in non-CNS sites, or a resistant breast cancer subtype. METHODS: To determine the factors associated with clinical CNS relapse, we examined response to neoadjuvant chemotherapy (chemosensitivity), time to relapse and sites of relapse in a cohort of 140 patients without evidence of metastasis at presentation. RESULTS: At 5 years (interquartile range 3-6 years), 44 (31%) patients developed distant metastases, including 13 with CNS metastases. CNS relapse was early (median 24 months after diagnosis) and associated with relapse in bone and liver, suggesting hematogenous dissemination. Those with CNS relapse were younger at diagnosis (40 versus 49 years) and more likely to have lymphovascular invasion in the primary tumor compared with non-CNS metastases. Response to neoadjuvant chemotherapy was not different (69% versus 73% response rate) between the two groups. Extent of residual disease after chemotherapy was strongly associated with relapse outside the CNS but not CNS relapses. The CNS was an isolated or dominant site of metastasis in 8 of 13. Despite treatment, most patients with CNS involvement died of neurologic causes a median of 6 months later. CONCLUSION: Breast cancers that develop CNS metastases differ from those that develop metastases elsewhere. Both tumor behavior and reduced chemotherapy accessibility to the CNS may contribute to increased CNS involvement in breast cancer patients treated with multimodality therapy.

PMID: 15609130 [PubMed - indexed for MEDLINE]

9. Carey LA, Ewend MG, Metzger R et al. Central nervous system metastases in women after multimodality therapy for high risk breast cancer. Breast Cancer Res Treat. 2004; 88: 273–280.

10. Bendell JC, Domchek S, Burstein HJ et al. Central nervous system metastases in
women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 2003; 97: 2972–2977.

11. Burstein HJ, Lieberman G, Slamon DJ et al. Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy. Ann Oncol. 2005; 16(11):1772–1777.

12. Dawson SJ, Ranieri NF, Snyder RD et al. Central nervous system metastases in
women with HER-2 positive metastatic breast cancer after treatment with trastuzumab. Asia Pac J Clin Oncol. 2006; 2: 50–56.

13. Minn AJ, Kang Y, Serganova I et al. Distinct organ-specific metastatic potential of
individual breast cancer cells and primary tumors. J Clin Invest. 2005; 115:44–55.

14. Pestalozzi BC, Brignoli S. Trastuzumab in CSF. J Clin Oncol. 2000; 18: 2350–2351.

Research May Provide Potential Target For New Therapies To Limit Metastasis Of Primary Breast Cancers


http://www.medicalnewstoday.com/articles/182239.php

15 Mar 2010

Researchers at the University of Maryland Marlene and Stewart Greenebaum Cancer Center have discovered that "microtentacles," or extensions of the plasma membrane of breast cancer cells, appear to play a key role in how cancers spread to distant locations in the body. Targeting these microtentacles might prove to be a new way to prevent or slow the growth of these secondary cancers, the scientists say.

They report in an article to be published online March 15, 2010, in the journal Oncogene that a protein called "tau" promotes the formation of these microtentacles on breast tumor cells which break away from primary cancers and circulate in the bloodstream. While twisted remnants of tau protein have been seen in the brain tissue of patients with Alzheimer's disease, this is the first report that tau could play a role in tumor metastasis by changing the shape of cancer cells. These tau-induced microtentacles can help the cells reattach to the walls of small blood vessels to create new pockets of cancer.

researchers analyzed breast tumor cells from 102 patients and found that 52 percent had tau in their metastatic tumors and 26 percent (27 patients) showed a significant increase in tau as their cancer progressed. Twenty-two of these patients even had tau in metastatic tumors despite having none in their primary tumors.

Oncogene. 2010 Jun 3;29(22):3217-27. Epub 2010 Mar 15.
Metastatic breast tumors express increased tau, which promotes microtentacle formation and the reattachment of detached breast tumor cells.

Matrone MA, Whipple RA, Thompson K, Cho EH, Vitolo MI, Balzer EM, Yoon JR, Ioffe OB, Tuttle KC, Tan M, Martin SS.
Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.


TEXT

Abstract

The cytoskeletal organization of detached and circulating tumor cells (CTCs) is currently not well defined and may provide potential targets for new therapies to limit metastatic tumor spread. In vivo, CTCs reattach in distant tissues by a mechanism that is tubulin-dependent and suppressed by polymerized actin. The cytoskeletal mechanisms that promote reattachment of CTCs match exactly with the mechanisms supporting tubulin microtentacles (McTN), which we have recently identified in detached breast tumor cells. In this study, we aimed to investigate how McTN formation is affected by the microtubule-associated protein, tau, which is expressed in a subset of chemotherapy-resistant breast cancers. We demonstrate that endogenous tau protein localizes to McTNs and is both necessary and sufficient to promote McTN extension in detached breast tumor cells. Tau-induced McTNs increase reattachment of suspended cells and retention of CTCs in lung capillaries. Analysis of patient-matched primary and metastatic tumors reveals that 52% possess tau expression in metastases and 26% display significantly increased tau expression over disease progression. Tau enrichment in metastatic tumors and the ability of tau to promote tumor cell reattachment through McTN formation support a model in which tau-induced microtubule stabilization provides a selective advantage during tumor metastasis.

PMID: 20228842 [PubMed - in process]

In summary, MAPs have powerful implications for chemotherapy efficacy and metastatic progression. Tau provides taxane-resistance through binding-competition on microtubules (Wagner et al., 2005). Furthermore, taxanes have been determined to increase CTCs by 10 000-fold among breast cancer patients (Camara et al.,2007). As CTC persistence is indicative of an increased risk of disease recurrence (Janni et al., 2005), and tau increases the trapping and reattachment of detached breast tumor cells, pathological evaluation of tau may benefit patients by minimizing metastasis through CTC mobilization. Elucidating the role of tau and other MAPs in cancer may lead to new therapeutics that target MAP expression or the regulation of MAPtubulin interactions. It has been suggested that the expression of neuronal MAPs in non-neuronally derived cancers speak to their origin from stem cell-like precursors (Bhat and Setaluri, 2007). This raises the potential for collaboration between the neurodegenerative and cancer drug fields. Aberrant regulation of tau leads to neurodegenerative tauopathies. Consequently, numerous tau-targeted compounds have been characterized, some of which are current therapeutics (Bulic et al.,2009). Promising are two drugs, aziridinylbenzoquinone and albendazole, which can reduce tau expression by 38 and 52%, respectively, without detectable cytotoxicity (Dickey et al., 2006). As cancer therapeutics, these and other anti-tau drugs may hold potential to inhibit tumor metastasis by reducing tau-induced McTNs.

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

Ikeda H, Taira N, Hara F, Fujita T, Yamamoto H, Soh J, Toyooka S, Nogami T, Shien T, Doihara H, Miyoshi S.
Corresponding author: Naruto Taira ntaira@md.okayama-u.ac.jp

FREE TEXT


ABSTRACT:

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

PMID: 20579400 [PubMed - as supplied by publisher]

Several mechanisms of taxane resistance have been described, including overexpression of the drug efflux pump MDR-1/P-gp, HER-2 overexpression, tubulin mutation, and variable expression of tubulin isotypes and stathmin [4, 7-12]. Microtubule-associated protein-tau (MAPT), which is implicated in the pathogenesis of Alzheimer’s disease, is associated with another mechanism of taxane resistance. MAPT binds to both the outer and inner surfaces of microtubules, leading to tubulin assembly and microtubule stabilization. Since
taxanes also bind to the inner surface of microtubules, MAPT obstructs the function of the drug [5, 6, 13, 14].
Rouzier et al. found that low MAPT expression was associated with higher rates of a pathologic complete response to preoperative paclitaxel and 5-fluorouracil, doxorubicin, cyclophosphamide (paclitaxel/FAC) chemotherapy [5]. This group also showed that MAPT overexpression was correlated with resistance to paclitaxel and that knockdown of MAPT with small interfering RNA (siRNA) reversed the resistance to taxanes in vitro [5].

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Hormonal drugs play an important role in breast cancer therapy. The selective ER inhibitor, fulvestrant, inhibits estrogen signaling through the ER in two ways: by competing with estradiol binding to the ER, and by increasing the turnover of ER to decrease the ER protein level in breast cancer cells. In contrast, tamoxifen, a selective ER modulator, is an ER antagonist but often displays estrogen-like agonist activity [22-24].
Previous in vitro studies show that tamoxifen has an antagonistic effect on anti-cancer drugs [25, 26]. Several clinical studies that used tamoxifen for hormone therapy have found that it has an antagonistic effect on chemotherapy drugs when it is used concurrently with them, and that the results of the combined use of tamoxifen with chemotherapy drugs is inferior, compared with using the drugs sequentially [27-30]. The effect of combination treatment using other modern hormone therapies, such as aromatase inhibitors or
fulvestrant, has not been examined thoroughly.

Our results suggested that the effect of tamoxifen on ER signaling differs depending on the dose. MAPT protein expression was increased at low concentrations of tamoxifen of 500 nM - 1 μM, but decreased at higher concentrations. Several factors associated with resistance to chemotherapy via regulation by ER signaling have been identified [4, 22, 38-40]. Tamoxifen is thought to exert an antagonistic effect in concomitant use with chemotherapeutic drugs by increasing the expression of these factors via an agonistic effect on the ER. Active metabolites of tamoxifen also have different functions compared with the parent drug [41-43], and more detailed studies are needed to
determine how tamoxifen and its metabolites influence chemotherapy in vivo and in vitro.
Fulvestrant decreased ER and MAPT expression at all concentrations. An MTS assay, flow cytometry, and immunofluorescence all showed that the combination of fulvestrant and taxanes had a synergistic effect, consistent with the finding of Sui et al. that fulvestrant combined with paclitaxel was effective in breast cancer cells in vitro [24]. Fulvestrant assists taxane function by downregulating the ER and ER-regulated factors associated with taxane resistance, and the combination of fulvestrant with taxanes increases the sensitivity of MAPT- and ER-positive breast cancer cells to taxanes.
ER-positive breast cancers clinically show a lower sensitivity to chemotherapy than do ER-negative breast cancers. This may be caused by the ER itself or by ER modulation of factors that result in resistance to chemotherapy. Our study indicates that the combination of modern hormone therapy with modern chemotherapy may become an effective therapy to ER-positive breast cancers.